KR20050026074A - Antimicrobial aza-bicyclic derivatives, their compositions and uses - Google Patents

Abstract

Compounds of the following formula (I) are effective antimicrobial agents.

Description

ANTIMICROBIAL AZA-BICYCLIC DERIVATIVES, THEIR COMPOSITIONS AND USES}

The present invention relates to novel antimicrobial compounds, compositions thereof and uses thereof.

Chemical and medical literature describes compounds that are antimicrobial, ie capable of destroying or inhibiting the growth or replication of microorganisms, such as bacteria. For example, such antimicrobials and other antimicrobial agents are described in Antibiotics, Chemotherapeutics, and Antibacterial Agents for Disease Control (M. Grayson, editor, 1982), and E. Gale et al., The Molecular Basis of Antibiotic Action 2d edition ( 1981).

The mechanism of action of these antimicrobials varies. However, they are generally thought to function in one or more of the following ways: by inhibition of cell wall synthesis or repair, by alteration of cell wall permeability, by inhibition of protein synthesis, or by inhibition of nucleic acid synthesis. For example, beta-lactam antibacterial agents act through the inhibition of essential penicillin binding protein (PBP) in bacteria, which is responsible for cell wall synthesis. As another example, quinolone acts at least in part by inhibiting the synthesis of DNA to prevent cells from replicating.

The pharmacological properties of the antimicrobial agents and their suitability for any given clinical use vary. For example, antimicrobial agents (and members within one class) may be: 1) their relative efficacy against different types of microorganisms, 2) their sensitivity to exhibiting microbial resistance, and 3) their pharmacological properties such as their May differ in bioavailability and biodistribution. Thus, the selection of an appropriate antimicrobial agent (or other antimicrobial agent) in a given clinical situation requires the analysis of a number of factors, including the type of organism involved, the desired method of administration, the location of infection to be treated and other considerations.

However, many of these attempts to produce improved antimicrobial agents have produced multipurpose results. Indeed, very few clinically acceptable antimicrobial agents are produced in terms of antimicrobial activity spectrum, avoidance of microbial resistance and pharmacological properties. Thus, there is a continuing need for a broad spectrum of antimicrobial agents that are effective against resistant microorganisms.

It is known in the art that some 1,4-dihydroquinolone, naphthyridine or related heterocyclic moieties have antimicrobial activity, the following references, ie R. Albrecht, Prog. Drug Research, Vol. 21, p. 9 (1977), J. Wolfson et al., "The Fluoroquinolones: Structures, Mechanisms of Action and Resistance, and Spectra of Activity In Vitro", Antimicrob. Agents and Chemother., Vol. 28, p. 581 (1985), G. G. Klopman et al., Antimicrob. Agents and Chemother., Vol. 31, p. 1831 (1987), M. P. Wentland et al., Ann. Rep. Med. Chem., Vol. 20, p. 145 (1986), J. B. Cornett et al., Ann. Rep. Med. Chem., Vol. 21, p. 139 (1986), P. In B. Fernandes et al., Ann. Rep. Med. Chem., Vol. 22, p. 117 (1987), A. Koga, et al., "Structure-Activity Relationships of Antibacterial 6,7- and 7,8-Disubstituted 1-alkyl-1,4-dihydro-4-oxoquinoline-3-carboxylic Acids", J. Med. Chem., Vol. 23, pp. 1358-1363 (1980), J.M. Domagala et al., J. Med. Chem., Vol. 31, p. 991 (1988), T. Rosen et al., J. Med. Chem., Vol. 31, p. 1586 (1988), T. Rosen et al., J. Med. Chem., Vol. 31, p. 1598 (1988), B. Ledoussal et al., "Non 6-Fluoro Substituted Quinolone Antibacterials: Structure and Activity", J. Med Chem., Vol. 35, p. 198-200 (1992), J. M. Domagala et al., "Quinolone Antibacterials Containing the New 7- [3- (1-Aminoethylethyl) -1-pyrrolidinyl] Side Chain: The Effects of the 1-Aminoethyl Moiety and Its Stereochemical Configurations on Potency and in Vivo Efficacy" , J. Med. Chem., Vol. 36, pp. 871-882 (1993), Hagen et al., "Synthesis and Antibacterial Activity of New Quinolones Containing a 7- [3- (1-Amino-1-methylethyl) -1-pyrrolidinyl] Moiety. Gram Positive Agents with Excellent Oral Activity and Low Side-Effect Potential ", J. Med. Chem. Vol. 37, pp. 733-738 (1994), V. Cecchetti et al., "Studies on 6-Aminoquinolines: Synthesis and Antibacterial Evaluation of 6-Amino-8-methylquinolones", J. Med. Chem., Vol. 39, pp. 436-445 (1996), V. Cecchetti et al., "Potent 6-Desfluoro-8-methylquinolones as New Lead Compounds in Antibacterial Chemotherapy", J. Med. Chem., Vol. 39, pp. 4952-4957 (1996), Hong et al., "Novel 5-Amino-6-methylquinolone Antibacterials: a New Class of Non-6-fluoroquinolones", Bioorg. of Med. Chem. Let., Vol. 7, pp. 1875-1878 (1997), US Pat. No. 4,844,902 to Grohe, Jul. 4, 1989, US Pat. No. 5,072,001 to Hagen and Suto, Dec. 10, 1991; Demuth and White, U.S. Patent No. 5,328,908, issued July 12, 1994; Bartel, et al., US Pat. No. 5,457,104, issued October 10, 1995, issued September 17, 1996. U.S. Patent No. 5,556,979 to Philipps et al., European Patent Application No. 572,259 to Ube Ind., Published December 1, 1993, Toyama Chemical Company, published May 28, 1997. European Patent Application No. 775,702 to Toyama Chem. Co., and Japanese Patent Publication No. 62 / 255,482 to Kyorin Pharm. Co., published March 1, 1995.

Examples of bacterial infections that are resistant to antibiotic therapy have been reported in the past, and they are now a significant threat to public health in the developed world. The development of microbial resistance (probably as a result of prolonged use of antimicrobials over long periods of time) is of increasing concern in medical science. Tolerance can be defined as the presence of organisms within a given population of microbial species that are less sensitive to the action of a given antimicrobial agent. Such resistance is of particular concern in environments such as hospitals and nursing homes where relatively high rates of infection and the use of enormous antimicrobials are common. See, eg, W. Sanders, Jr. et al., "Inducible Beta-lactamases: Clinical and Epidemiologic Implications for Use of Newer Cephalosporins", Reviews of Infectious Diseases, p. 830 (1988).

Pathogenic bacteria include inactivation of antibiotics by bacterial enzymes (eg, b-lactamase that hydrolyzes penicillin and cephalosporin); Removal of antibiotics using an effluent pump; Modification of the target of the antibiotic via mutation and gene recombination (eg penicillin resistance in Neiserria gonorrhoeae); And through a number of unique mechanisms, including obtaining easily movable genes from external sources to generate resistant targets (eg, methicillin resistance in Staphylococcus aureus). It is known to acquire resistance. There are certain Gram-positive pathogens such as vancomycin resistant Enterococcus faecium that are resistant to virtually all commercially available antibiotics. Thus, existing antimicrobials have limited capacity in overcoming the threat of resistance.

In addition to overcoming resistance, many commercially available quinolone antibiotics have undesirable side effects. For example, gatifloxacin ((±) -1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7- (3-methyl-1-piperazinyl)- 4-oxo-3-quinoline carboxylic acid) has been reported to exhibit clastogenicity (Jounal of Antimicrobial Chemotherapy, Vol. 33, pp. 685-706 (1994). Antimicrobial agents have shown undesirable side effects such as clastogenecity.

Therefore, it is advantageous to provide antimicrobial agents with useful properties that include advantageous clastogenecity profiles, which can be used against resistant microorganisms.

Summary of the Invention

The inventors have discovered novel quinolone-based and related compounds which are effective against resistant microorganisms and offer significant activity advantages over the prior art, including the promising clastogenecity profile. In particular, the present invention relates to compounds having a structure according to formula (I), or optical isomers, diastereomers or enantiomers thereof, pharmaceutically acceptable salts, hydrates, or biohydrolysable esters, amides or imides thereof:

(I)

here,

(A) (1) A ¹ is selected from -N- and -C (R ⁸ )-, R ⁸ is hydrogen, halo, C ₁ to about C ₆ alkyl, C <F 2 to about C ₆ alkene Or alkane and C ₁ to about C ₆ alkoxy, all such alkyl, alkene, alkane and alkoxy moieties being unsubstituted or substituted with 1 to about 3 fluoro;

   (2) a, b and c are each independently a single or double bond;

   (3) (a) X is one of -C- or -N-; (i) when X is -C-, a is a double bond and b is a single bond, and (ii) when X is -N-, a is a single bond and b is a double bond;

(b) Y is selected from -N (R ¹ )-and -CR ° R ^1- ; R ° is hydrogen or absent, when b is a single bond, R ° is hydrogen and when b is a double bond, R ° is absent;

(c) Z is selected from -C (COR ³ )-, -N (R ³ )-and -N (NHR ³ )-; (i) when Z is -C (COR ³ )-, c is a double bond, and (ii) when Z is one of -N (R ³ )-or -N (NHR ³ )-, c is a single bond But only

(d) Y is -N (R ¹ )-only when X is -C-;

(e) Y is -C (R ¹ )-only when X is -N- and Z is -C (COR ³ )-;

(f) Z is -N (OH)-or -N (NHR ³ )-only if X is -C-, Y is -N (R ¹ )-and A ¹ is -C (R ⁸ )- One;

(4) R ¹ is C ₃ to about C ₆ cycloalkyl, C ₃ to about C ₆ heterocycloalkyl, C ₁ to about C ₆ alkyl, C ₂ to about C ₆ alkene or alkane, C ₁ To about C ₆ alkyloxy, 6-membered aryl and 6-membered heteroaryl, all such alkyl, alkenes, alkanes, alkoxy, cycloalkyl, aryl and heteroaryl are unsubstituted or substituted with 1 to 3 fluoro All such aryl and heteroaryl are also unsubstituted or substituted with one hydroxy at the 4-position;

(5) R ² is hydrogen, double bond oxygen, C ₁ to about C ₆ alkyl, C ₂ to about C ₆ alkene or alkane, C ₁ to about C ₆ alkoxy and C ₁ to about C ₆ thio Selected from alkyl, provided that R ² is double bond oxygen only when Z is —N (OH) — or —N (NHR ³ ) —;

(6) R ³ is hydrogen, hydroxy, C ₁ to about C ₆ alkyl, C ₂ to about C ₆ alkene or alkane, C ₁ to about C ₆ alkoxy and C ₁ to about C ₆ thioalkyl Is selected from;

(7) R ⁵ is selected from hydrogen, hydroxy, amino, halo, alkoxy of C ₁ to about C ₆ alkyl, C ₂ to about C ₄ alkene, or alkyne, and C ₁ to about C _4, all of these Alkyl, alkene, alkane and alkoxy moieties are unsubstituted or substituted with 1 to 3 fluoro;

(8) R ⁶ is selected from hydroxy, aminocarbonyl, fluoro, chloro, bromo, cyano, alkyl of C ₁ to about C ₂ and alkenyl or alkynyl of C ₂ to about C ₄ , All such alkyl, alkenyl and alkynyl moieties are unsubstituted or substituted with from 1 to about 3 fluoro;

(9) R ⁷ and R ^{7 '} are each independently

(a) hydrogen, C ₁ to about C ₆ alkyl, C ₂ to about C ₆ alkene or alkane, C ₁ to about C ₆ alkoxy, C ₁ to about C ₆ alkylthio and C ₁ to about C ₆ is selected from heteroalkyl, provided that R ⁷ and R ^{7 '} are not both hydrogen;

(b) R ⁷ and R ^{7 '} combine to form a C ₃ to about C ₆ cycloalkyl or heterocyclic ring comprising the carbon atoms to which they are attached;

      (c) all such alkyl, alkene, alkane, alkoxy, alkylthio, heteroalkyl, cycloalkyl and heterocyclic moieties are unsubstituted or substituted with 1 to 3 fluoro;

(10) R ⁹ and R ^{9 '} are each independently selected from hydrogen and C ₁ to about C ₃ alkyl, or R ⁹ and R ^9' are C ₃ to about C ₆ containing a nitrogen atom to which they are bonded To form a heterocyclic ring of;

(11) R ¹⁰ represents a moiety on a piperidine ring other than R ⁷ , R ^{7 ′} and —NR ⁹ R ^{9 ′} , wherein each R ¹⁰ is independently hydrogen, alkyl of C ₁ to about C ₆ , C ₂ to about C ₆ alkene or alkane, C ₁ to about C ₆ alkoxy and C ₃ -C ₆ cycloalkyl, all such alkyl, alkene, alkane, alkoxy and cycloalkyl moieties are unsubstituted or To 3 fluoro;

(B) when A ¹ is -C (R ⁸ )-, X is -C- and Y is -N (R ¹ )-, R ⁸ and R ¹ can be joined to form a 6-membered heterocyclic ring Where R ² , R ³ , R ⁵ , R ⁶ , R ⁷ , R ^{7 '} , R ⁹ , R ^{9 '} and R ¹⁰ are as described in (A);

(C) If A ¹ is -C (R ⁸ )-, X is -C-, Y is -N (R ¹ )-and Z is ?? C (COR ³ ), then R ¹ and R ² are joined to mono Cyclic or bicyclic heterocyclic rings may be formed wherein R ³ , R ⁵ , R ⁶ , R ⁷ , R ^{7 ′} , R ⁸ , R ⁹ , R ^{9 '} and R ¹⁰ are as described in (A);

(D) If A ¹ is -C (R ⁸ )-, X is -C-, Y is -N (R ¹ )-and Z is -C (COR ³ ), then R ² and R ³ are bonded to carbonyl To a 5-membered heterocycloalkyl substituted with a moiety, wherein R ¹ , R ⁵ , R ⁶ , R ⁷ , R ^{7 ′} , R ⁸ , R ⁹ , R ^{9 '} and R ¹⁰ are as described in (A).

It is also contemplated that compounds in which the compounds of the invention are incorporated or that use the compounds of the invention as starting materials are also within the scope of the invention.

The compounds of the present invention, and compositions containing the compounds, have been found to be effective antimicrobial agents against a wide range of pathogenic microorganisms and have advantages in terms of low sensitivity to microbial resistance, reduced toxicity, and improved pharmacological properties.

In addition, the compounds of the present invention, and compositions containing the present compounds, have been found to exhibit promising clastogenecity profiles.

I. Terms and Definitions:

The following is a list of term definitions used herein.

“Acyl” is a radical formed by removing hydroxy from a carboxylic acid (ie R—C (═O) —). Preferred acyl groups include (eg) acetyl, formyl and propionyl.

"Alkyl" is a saturated hydrocarbon chain having 1 to 15 carbon atoms, preferably 1 to 10, more preferably 1 to 4 carbon atoms. "Alkenes" are hydrocarbons having one or more (preferably only one) carbon-carbon double bonds and having 2 to 15 carbon atoms, preferably 2 to 10, more preferably 2 to 4 carbon atoms It is a chain. Hydrocarbons having one or more (preferably only one) carbon-carbon triple bonds and having from 2 to 15 carbon atoms, preferably from 2 to 10, more preferably from 2 to 4 carbon atoms It is a chain. Alkyl, alkene and alkane chains (collectively referred to as "hydrocarbon chains") may be straight chained or branched and may be unsubstituted or substituted. Preferred branched alkyl, alkene and alkane chains have one or two branches, preferably one branch. Preferred chains are alkyl. Each of the alkyl, alkene and alkane hydrocarbon chains may be unsubstituted or substituted with 1 to 4 substituents; Preferred chains upon substitution are mono-, di- or trisubstituted. Each of the alkyl, alkene and alkane hydrocarbon chains is halo, hydroxy, aryloxy (eg phenoxy), heteroaryloxy, acyloxy (eg acetoxy), carboxy, aryl (eg Phenyl), heteroaryl, cycloalkyl, heterocycloalkyl, spirocycle, amino, amido, acylamino, keto, thioketo, cyano or any combination thereof. Preferred hydrocarbon groups include methyl, ethyl, propyl, isopropyl, butyl, vinyl, allyl, butenyl, and exomethyleneyl.

"Alkoxy" is an oxygen radical having a hydrocarbon chain substituent, wherein the hydrocarbon chain is alkyl or alkenyl (ie, -O-alkyl or -O-alkenyl). Preferred alkoxy groups include (eg) methoxy, ethoxy, propoxy and allyloxy.

"Alkylthio" is -S-alkyl (eg, -S-CH ₃ ).

In addition, as referred to herein, "lower" alkoxy, alkylthio, alkyl, alkene or alkane moieties (eg, "lower alkyl") are 1-6, preferably for alkyl, alkoxy and alkylthio Preferably a chain consisting of 1 to 4 carbon atoms and 2 to 6, preferably 2 to 4 carbon atoms in the case of alkene and alkane.

"Amino" refers to primary (-NH ₂ ), secondary (-NH (alkyl), also referred to herein as "alkylamino") or tertiary (-N (alkyl) _2, also referred to herein as "dialkylamino" Disappears).

"Aminoalkyl" means an alkyl moiety substituted with an amino, alkyl amino or dialkyl amino group (eg, -CH ₂ NH ₂ , -CH ₂ CH ₂ NH _2, -CH ₂ NHCH ₃ , -CH ₂ N (CH ₃ ) ₂ ).

"Aryl" is an aromatic hydrocarbon ring. Aryl rings are monocyclic or fused bicyclic ring systems. Monocyclic aryl rings contain six carbon atoms in the ring. Monocyclic aryl rings are also referred to as phenyl rings. Bicyclic aryl rings contain 8 to 17 carbon atoms, preferably 9 to 12 carbon atoms in the ring. Bicyclic aryl rings include ring systems in which one ring is aryl and the other ring is aryl, cycloalkyl, or heterocycloalkyl. Preferred bicyclic aryl rings include those in which a 5-, 6-, or 7-membered ring is fused to a 5-, 6- or 7-membered ring. The aryl ring may be unsubstituted or substituted with 1 to 4 substituents on the ring. Aryl is halo, cyano, nitro, hydroxy, carboxy, amino, acylamino, alkyl, heteroalkyl, haloalkyl, phenyl, aryloxy, alkoxy, heteroalkyloxy, carbamyl, haloalkyl, methylenedioxy, heteroaryl Oxy or any combination thereof. Preferred aryl rings include naphthyl, tolyl, xylyl and phenyl. Most preferred aryl ring radical is phenyl.

"Aryloxy" is an oxygen radical (ie -O-aryl) having an aryl substituent. Preferred aryloxy groups include (eg) phenoxy, naphthyloxy, methoxyphenoxy and methylenedioxyphenoxy.

"Carbocyclic ring" includes both cycloalkyl and aryl moieties as the term is defined herein.

"Carbonyl" is -C (= 0)-.

"Cycloalkyl" is a saturated or unsaturated hydrocarbon ring. Cycloalkyl rings are not aromatic. Cycloalkyl rings are monocyclic or are fused, spiro, or bridged bicyclic ring systems. Monocyclic cycloalkyl rings contain from about 3 to about 9 carbon atoms, preferably from 3 to 7 carbon atoms in the ring. The bicyclic cycloalkyl ring contains 7 to 17 carbon atoms, preferably 7 to 12 carbon atoms in the ring. Preferred bicyclic cycloalkyl rings include those in which a 4-, 5-, 6- or 7-membered ring is fused to a 5-, 6-, or 7-membered ring. Cycloalkyl rings may be unsubstituted or substituted with 1 to 4 substituents on the ring. Cycloalkyl may be substituted with halo, cyano, alkyl, heteroalkyl, haloalkyl, phenyl, keto, hydroxy, carboxy, amino, acylamino, aryloxy, heteroaryloxy or any combination thereof. Preferred cycloalkyl rings include cyclopropyl, cyclopentyl, and cyclohexyl.

"Halo" or "halogen" is fluoro, chloro, bromo or iodo. Preferred halo are fluoro, chloro and bromo, more preferred are typically chloro and fluoro, in particular fluoro.

"Haloalkyl" is a straight chain, branched or cyclic hydrocarbon substituted with one or more halo substituents. Preferred are C ₁ -C ₁₂ haloalkyl; More preferred are C ₁ -C ₆ haloalkyl; Even more preferred is C ₁ -C ₃ haloalkyl. Preferred halo substituents are fluoro and chloro. Most preferred haloalkyl is trifluoromethyl.

"Heteroatoms" are nitrogen, sulfur or oxygen atoms. Groups containing more than one heteroatom may comprise different heteroatoms.

"Heteroalkyl" is a saturated or unsaturated chain comprising carbon and one or more heteroatoms, wherein the two heteroatoms are not adjacent. Heteroalkyl chains comprise from 2 to 15, preferably from 2 to 10, more preferably from 2 to 5 member atoms (carbon and heteroatoms) in the chain. For example, alkoxy (ie -O-alkyl or -O-heteroalkyl) radicals are included in the heteroalkyl. Heteroalkyl chains may be straight or branched chain. Preferred branched heteroalkyls have one or two branches, preferably one branch. Preferred heteroalkyls are saturated. Unsaturated heteroalkyls have one or more carbon-carbon double bonds and / or one or more carbon-carbon triple bonds. Preferred unsaturated heteroalkyls have one or two double bonds or one triple bond, more preferably one double bond. Heteroalkyl chains may be unsubstituted or substituted with 1 to 4 substituents. Preferred substituted heteroalkyls are mono-, di- or tri-substituted. Heteroalkyl is lower alkyl, haloalkyl, halo, hydroxy, aryloxy, heteroaryloxy, acyloxy, carboxy, monocyclic aryl, heteroaryl, cycloalkyl, heterocycloalkyl, spirocycle, amino, acylamino, amino Can also be substituted with keto, thioketo, cyano or any combination thereof.

"Heteroaryl" is an aromatic ring containing carbon atoms and 1 to about 6 heteroatoms in the ring. Heteroaryl rings are monocyclic or fused bicyclic ring systems. Monocyclic heteroaryl rings contain from about 5 to about 9 member atoms (carbon and heteroatoms), preferably 5 or 6 member atoms in the ring. Bicyclic heteroaryl rings contain from 8 to 17 member atoms, preferably from 8 to 12 member atoms in the ring. Bicyclic heteroaryl rings include ring systems in which one ring is heteroaryl and the other ring is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl. Preferred bicyclic heteroaryl ring systems include those in which a 5-, 6-, or 7-membered ring is fused to a 5-, 6- or 7-membered ring. Heteroaryl rings may be unsubstituted or substituted with 1 to 4 substituents on the ring. Heteroaryl may be substituted with halo, cyano, nitro, hydroxy, carboxy, amino, acylamino, alkyl, heteroalkyl, haloalkyl, phenyl, alkoxy, aryloxy, heteroaryloxy or any combination thereof. Preferred heteroaryl rings include but are not limited to:

“Heteroaryloxy” is an oxygen radical having a heteroaryl substituent (ie, —O-heteroaryl). Preferred heteroaryloxy groups are (for example) pyridyloxy, furanyloxy, (thiophene) oxy, (oxazole) oxy, (thiazole) oxy, (isoxazole) oxy, pyrimidinyloxy, pyrazinyloxy And benzothiazolyloxy.

"Heterocycloalkyl" is a saturated or unsaturated ring containing carbon atoms and 1 to about 4 (preferably 1 to 3) heteroatoms in the ring. Heterocycloalkyl rings are not aromatic. Heterocycloalkyl rings are monocyclic or bicyclic ring systems. Monocyclic heterocycloalkyl rings contain from about 3 to about 9 member atoms (carbon and heteroatoms), preferably 5 to 7 member atoms in the ring. Bicyclic heterocycloalkyl rings contain 7 to 17 member atoms, preferably 7 to 12 member atoms, in the ring. Bicyclic heterocycloalkyl rings contain about 7 to about 17 ring atoms, preferably 7 to 12 ring atoms. The bicyclic heterocycloalkyl ring can be a fused, spiro or bridged ring system. Preferred bicyclic heterocycloalkyl rings include those in which a 5-, 6-, or 7-membered ring is fused to a 5-, 6- or 7-membered ring. Heterocycloalkyl rings may be unsubstituted or substituted with 1 to 4 substituents on the ring. Heterocycloalkyl is halo, cyano, hydroxy, carboxy, keto, thioketo, amino, acylamino, acyl, amido, alkyl, heteroalkyl, haloalkyl, phenyl, alkoxy, aryloxy or any combination thereof. Can be substituted. Preferred substituents on heterocycloalkyl include halo and haloalkyl. Preferred heterocycloalkyl rings include, but are not limited to:

"Heterocyclic ring" includes both heterocycloalkyl and heteroaryl moieties as the term is defined herein.

A "spirocycle" is an alkyl or heteroalkyl diradical substituent of alkyl or heteroalkyl, the diradical substituents are initially attached, the diradical substituents form a ring, the ring having 4 to 8 member atoms (carbon Or heteroatom), preferably 5 or 6 member atoms.

"Lower" alkoxy, alkylthio, alkyl, alkene or alkane moieties (eg, "lower alkyl") may be from 1 to 6, preferably from 1 to 4 carbon atoms, for alkyl, alkoxy and alkylthio, and In the case of alkene and alkane it is a chain consisting of 2 to 6, preferably 2 to 4 carbon atoms.

Alkyl, heteroalkyl, cycloalkyl and heterocycloalkyl groups may be substituted with hydroxy, amino and amido groups as described above, but the following is not considered in the present invention:

1.enol (OH attached to alkene carbon).

2. Amino groups attached to carbons bearing double bonds, except for vinyl position amides.

3. More than one hydroxy, amino or amido attached to a single carbon unless two nitrogen atoms are attached to a single carbon atom and all three atoms are member atoms in a heterocycloalkyl ring.

4. Hydroxy, amino or amido with heteroatoms also attached to the attached carbon.

5. Hydroxy, amino or amido with halogen attached to carbon also attached.

A “pharmaceutically acceptable salt” is a cationic salt formed on any acidic (eg carboxyl) group on a compound of the invention, or any basic (eg, amino, alkylamino, dialkylamino, mor Filino, etc.). Since many of the compounds of the present invention are zwitterionic, either salt is possible and acceptable. Many such salts are known in the art. Preferred cationic salts include alkali metal salts (eg sodium and potassium), alkaline earth metal salts (eg magnesium and calcium) and organic salts such as ammonio. Preferred anionic salts include halides, sulfonates, carboxylates, phosphates and the like. Addition salts that can provide optical centers where there is no optical center are also clearly included in such salts. For example, chiral tartrate salts can be prepared from the compounds of the present invention and this definition includes such chiral salts. Salts included are nontoxic in amounts administered to a patient animal, mammal or human.

The compounds of the present invention are sufficiently basic to form acid addition salts. The compounds are useful in both free base form and in the form of acid addition salts, both forms are within the scope of the present invention. Acid addition salts are in some cases more convenient forms of use. Indeed, using the salt form essentially uses the active form in the base form. The acid used in the preparation of the acid addition salt preferably comprises producing a pharmaceutically acceptable salt when combined with the free base. Such salts have anions that are relatively nontoxic to animal organisms, such as mammals, at the medicinal dose of the salt such that the beneficial properties inherent in the free base are not compromised by any side effects due to the anions of the acid.

Examples of suitable acid addition salts are hydrochloride, hydrobromide, hydroiodide, sulfate, hydrogensulfate, acetate, trifluoroacetate, nitrate, citrate, fumarate, formate, stearate, succinate, maleate, malonate Adipates, glutarates, lactates, propionates, butyrates, tartrates, methanesulfonates, trifluoromethanesulfonates, p-toluenesulfonates, dodecyl sulfates, cyclohexanesulfates, and the like. It is not limited. However, other suitable pharmaceutically acceptable salts within the scope of the present invention are those derived from other inorganic and organic acids. Acid addition salts of basic compounds are prepared in several ways. For example, the free base can be dissolved in an aqueous alcohol solution containing the appropriate acid and the salt is isolated by evaporation of this solution. Alternatively, the acid addition salts can be prepared by reacting the free base with an acid in an organic solvent so that the salts separate directly. If the separation of salts is difficult, the salts can be precipitated with a second organic solvent or obtained by concentration of the solution.

Pharmaceutically acceptable salts of basic compounds are preferred, but all acid addition salts are within the scope of the present invention. All acid addition salts are useful as sources in free base form, even if the particular salt itself is desired only as an intermediate product. For example, when salts are formed only for purification or identification purposes, or when used as intermediates in preparing pharmaceutically acceptable salts by ion exchange procedures, the salts are clearly considered to be part of the present invention.

Such salts are well known to those skilled in the art and those skilled in the art can prepare any number of salts known in the art. Moreover, it is recognized that the skilled person may prefer one salt over another for reasons of solubility, stability, ease of formulation, and the like. Determination and optimization of such salts are within the scope of practice of the skilled person.

A "host" is a substrate capable of holding microorganisms and is preferably a living organism, more preferably an animal, more preferably a mammal, even more preferably a human.

"Biohydrolyzable amides" are aminoacyl, acylamino or other amides of the compounds of the present invention, wherein the amides do not essentially interfere with, and preferably do not interfere with, the activity of the compounds, or the amide is in vivo by the host. It is easily converted to produce the active compound.

"Biohydrolysable imide" is an imide of a compound of the invention, wherein the imide does not essentially interfere with the activity of the compound and preferably does not interfere, or the imide is readily converted in vivo by the host to the active compound. Create Preferred imides are hydroxyimides.

A "biohydrolysable ester" is an ester of a compound of the invention, wherein the ester does not essentially interfere with and preferably does not interfere with the antimicrobial activity of the compound, or the ester is readily converted in the host to produce the active compound. Many such esters are known in the art as described in US Pat. No. 4,783,443, which is incorporated herein by reference on Nov. 8, 1988 to Johnston and Mobashery. have. Such esters include lower alkyl esters, lower acyloxy-alkyl esters (eg, acetoxymethyl, acetoxyethyl, aminocarbonyloxymethyl, pivaloyloxymethyl and pivaloyloxyethyl esters), lactonyl esters ( Phthalidyl and thiopridyl esters), lower alkoxyacyloxyalkyl esters (eg, methoxycarbonyloxymethyl, ethoxycarbonyloxyethyl and isopropoxycarbonyloxyethyl esters), Alkoxyalkyl esters, choline esters and alkylacylaminoalkyl esters (eg, acetamidomethyl esters).

Examples of certain protective forms and other derivatives of compounds of Formula 1 are not intended to be limiting. Other useful protecting groups, salt forms and other applications are within the skill of the skilled person.

A "solvate" is a complex formed by the combination of a solute (eg, quinolone) and a solvent (eg, water). J. Honig et al., The Van Nostrand Chemist's Dictionary, p. 650 (1953). Pharmaceutically acceptable solvents used in accordance with the present invention are readily determined by those that do not interfere with the biological activity of the quinolone or quinolone derivatives (eg, water, ethanol, acetic acid, N, N-dimethylformamide and Other known)).

The terms "optical isomer", "stereoisomer", and "diastereoisomer" have the meanings recognized in standard techniques (see, eg, Hawley's Condensed Chemical Dictionary, 11th Ed.). Examples of certain protective forms and other derivatives of the compounds of the invention are not intended to be limiting. Other useful protecting groups, salt forms and other applications are within the skill of the skilled person.

Compounds of the invention may have one or more chiral centers. As a result, one optical isomer can be selectively prepared over the other, including diastereomers and enantiomers, for example, by use of chiral starting materials, catalysts or solvents, including diastereomers and enantiomers. Both stereoisomers or both optical isomers can be prepared at one time (racemic mixture). Compounds of the present invention may exist as diastereomers and enantiomers, or as mixtures of optical isomers including stereoisomers, racemic mixtures, and therefore known methods such as chiral resolution, chiral chromatography, and the like. Can be separated using.

It is also recognized that one optical isomer, including diastereomers and enantiomers, or stereoisomers, may have advantageous properties over others. Thus, when disclosing the claims of the present invention and describing the claims, both optical isomers, including diastereomers and enantiomers, or stereoisomers, which are substantially different when one racemic mixture is disclosed, are also described herein. It should be clearly considered that the disclosure and the claims are made.

As used herein, quinolone derivatives include prodrugs of quinolone or active drugs prepared from quinolone. Preferably, such derivatives include lactams (eg, cefem, carbacefem, penem, monolactam, etc.), optionally covalently bound to quinolone via a spacer. Such derivatives and methods of making and using them are apparent to those skilled in the art given the teachings herein.

II. compound:

The present invention includes compounds of formula I:

[Formula I]

(I)

Here, A ¹ , X, Y, Z, a, b, c, R ² , R ⁵ , R ⁶ , R ⁷ , R ^{7 '} , R ⁹ , R ^9' and R ¹⁰ are the above-mentioned outline paragraphs of the present invention. As defined in.

Referring to formula (I), the above description indicates that in one embodiment the nucleus of the compound (as defined in subpart (A)) comprises only two fused rings as represented. Alternatively, the nucleus of the compound comprises three or four fused rings as defined in subparts (B) to (D). Such alternative embodiments are represented below by Formula D, Formula E and Formula F, Formula G, and Formula H, respectively.

For each of the described embodiments, a non-limiting list of preferred compounds is also shown in the form of a table. In tablets, administration and the like, it is recognized that salts and other derivatives of these compounds are often used. Accordingly, pharmaceutically acceptable salts, hydrates or biohydrolyzable esters, amides or imides thereof are contemplated as part of the present invention and are intended to be included in the table.

Tables Ia-In include a non-limiting list of compounds of Formula A.

(A)

This compound has X being a carbon atom, Z is -C (COR ³ )-, R ² is hydrogen, R ³ is hydroxy, a represents a double bond, b represents a single bond, and c is a double bond A compound of formula I wherein the Y is N (R ¹ ) and no further fused ring is formed (ie, the compound of subpart (A)).

For the purposes of the present invention, Cy = cyclopropyl; F-Cy = 2-fluorocyclopropyl; 4F-Ph = 4-fluorophenyl; 2,4-diFPh = 2,4-difluorophenyl.

Tables IIa to IIh include a non-limiting list of compounds of Formula B.

 (B)

This compound is a compound of formula I wherein X is a nitrogen atom, a represents a single bond, b represents a double bond, c represents a double bond, and Y is -CR ^1- .

Tables IIIa to IIIo include compounds of Formula (C).

 (C)

This compound is a compound of formula (I) wherein X is carbon, Y is -N9 (R1)-, a is a double bond, b is a single bond, c is a single bond, and R2 is a double bond oxygen.

Table IV includes a non-limiting list of compounds according to formula D.

 (D)

This compound is a compound of formula I wherein Z is -C (COR3)-and R ¹ and R ⁸ are joined to form a six-membered heterocycloalkyl. Formula D is a substituted or unsubstituted -C- or -N- or D is -O- or S; R ¹³ and R ¹³ are independently selected from hydrogen and C1-C6 alkyl; E is defined to be selected from -O-, -S-, substituted or unsubstituted -C-, and substituted or unsubstituted -N-. In one embodiment, D is -O-. In one embodiment, E is —CH ₂ —. In one embodiment, R ¹³ is hydrogen and R ^{13 '} is C1-C6 alkyl, preferably methyl.

Tables Va and Vb include a non-limiting list of preferred compounds of formula D.

(The stereochemical properties at the carbon atoms bearing R ¹³ and R ^{13 ′} are preferably S-coordinated.)

With regard to formula E, the compound has the structure according to

(E)

This compound is a compound wherein Z is -C (COR3)-and R ¹ and R ² combine to form ring L, which is a mono- or bicyclic heterocycle comprising N.

Table VI includes a non-limiting list of preferred compounds of Formula F having the formula:

Table VII includes a non-limiting list of preferred compounds of formula G having the formula:

With regard to formula H, the compound has a structure according to the structure

(H)

This compound has Y wherein -N (R1)-, R ² and R ³ of formula I combine to form a 5-membered heterocycloalkyl, T is -O-, -S- and substituted or unsubstituted- A compound of formula I selected from N-. In one embodiment, T is -S-.

Table VIII contains a non-limiting list of preferred compounds of formula H.

The following are the parts associated with each of A ¹ , a, b and c, X, Y, Z, R ² , R ⁵ , R ⁶ , R ⁷ , R ^{7 ′} , R ⁹ , R ^{9 ′} and R ¹⁰ of Formula I An embodiment of the present invention will be described.

A ¹ is selected from -N- and -C (R ⁸ )-. In one embodiment, A ¹ is —C (R ⁸ ) —, R ⁸ is hydrogen, halo, C ₁ to about C ₆ alkyl, C ₂ to about C ₆ alkene or alkane and C ₁ to Selected from alkoxy of about C ₆ , all such alkyl, alkene, alkane and alkoxy moieties are unsubstituted or substituted with from 1 to about 3 fluoro. In one embodiment, R ⁸ is hydrogen. In one embodiment, R ⁸ is lower alkyl, preferably where R ⁸ has from 1 to about 2 carbon atoms, with methyl being preferred. In one embodiment, R ⁸ is lower alkene, preferred R ⁸ has 2 to about 4 carbon atoms, ethenyl is preferred. In one embodiment, R ⁸ is lower alkoxy, preferred R ⁸ has 1 to about 4 carbon atoms, with methoxy being preferred. In one embodiment, R ⁸ is lower alkylthio, preferred R ⁸ has 1 to about 4 carbon atoms, with methylthio being preferred. The alkyl and alkenes portion of all R ⁸ are unsubstituted or substituted with fluoro. In one embodiment, R ⁸ is halo and preferred R ⁸ is chloro and fluoro. In one embodiment, R ⁸ is chloro, methyl, methoxy, methylthio, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, and trifluoromethoxy Is selected from. In one embodiment, R ⁸ is selected from 1 to 3 fluoro substituted methyl, methoxy, methylthio, and chloro; In particular methoxy, methylthio or chloro.

a, b and c are each independently a single or double bond. In one embodiment, a is a double bond, b is a single bond, and c is a double bond. In one embodiment, a is a single bond, b is a double bond, and c is a double bond. In one embodiment, a is a double bond, b is a single bond, and c is a single bond.

X is selected from -C- or -N-. When X is -C-, a is a double bond and b is a single bond. In contrast, when X is -N-, a is a single bond and b is a double bond.

Y is selected from -N (R ¹ )-and -CR ° R ^1- . However, Y is N (R ¹⁾ only if X is -C-, X is -N- and Z is -C (COR ³⁾ - Y is -C (R ¹⁾ only if - a.

Z is selected from -C (COR ³ )-, -N (R ³ )-and -N (NHR ³ )-. When Z is -C (COR ³ )-, c is a double bond. In contrast, when Z is either -N (R ³ )-or -N (NHR ³ )-, c is a single bond. However, Z is either -N (R ³ )-or -N (NHR ³ )-only if X is -C-, Y is -N (R ¹ )-and A ¹ is -C (R ⁸ )-. One.

R ° is hydrogen or absent. When R ° is hydrogen, b is a single bond. In contrast, when R ° is absent, b is a double bond.

R ¹ is C ₃ to about C ₆ cycloalkyl, C ₃ to about C ₆ heterocycloalkyl, C ₁ to about C ₆ alkyl, C ₂ to about C ₆ alkene or alkane, C ₁ to about C ₆ alkyloxy, 6-membered aryl and 6-membered heteroaryl. All such alkyl, alkene, alkane, alkoxy, cycloalkyl, aryl and heteroaryl substituents are unsubstituted or substituted with 1 to 3 fluoro. All such aryls and heteroaryls are also unsubstituted or substituted with one hydroxy at the 4-position. In one embodiment, R ¹ is selected from C ₃ to about C ₆ cycloalkyl, C ₃ to about C ₆ heterocycloalkyl, C ₁ to about C ₄ alkyl and C ₂ to about C ₄ alkenes do. In one embodiment, R ¹ is selected from cyclopropyl, ethyl, t-butyl, 4-hydroxyphenyl and 2,4-difluorophenyl. In one embodiment, R ¹ is cycloalkyl of C ₃ to about C ₆ . In one embodiment, R ¹ is C ₁ to about C ₄ alkyl.

When R ¹ is cycloalkyl, preference is given to rings having from about 3 to about 5 ring carbon atoms, more preferably 3 ring carbon atoms. The R ¹ cycloalkyl moiety is preferably saturated or unsaturated with one double bond; More preferably R ¹ cycloalkyl is saturated. When R ¹ is linear lower alkyl, preference is given to R ¹ containing from 1 to about 2 carbon atoms, methyl and ethyl being preferred and most preferred is ethyl. When R ¹ is a lower linear alkene, preference is given to R ¹ containing from 2 to about 3 carbon atoms; Ethenyl is preferred. When R ¹ is branched lower alkyl or lower alkene, preference is given to R ¹ containing from 3 to about 4 carbon atoms; Branched lower alkyl is preferred; t-butyl is particularly preferred. All of the R ¹ moieties mentioned in this paragraph are unsubstituted or substituted. When R ¹ is substituted, preferably one or more fluorine atoms.

When R ¹ is 6-membered aryl or 6-membered heteroaryl aryl, the ring may be unsubstituted or from 1 to about 3 fluorine atoms, one amino group (preferably 3-position of the ring), one hydroxy (preferably Preferably, 4-position of the ring), or a combination of these substituents; Substituted phenyl is preferred. Preferred R ¹ moieties are selected from cyclopropyl, ethyl, phenyl substituted with 1 to 3 fluoro, and 4-hydroxyphenyl; More preferred are 2,4-difluorophenyl, in particular cyclopropyl or ethyl.

In one embodiment, R ¹ and R ⁸ together form a fused 6-membered heterocyclic ring.

R ² is selected from hydrogen, double bond oxygen, C ₁ to about C ₆ alkyl, C ₂ to about C ₆ alkene or alkane, C ₁ to about C ₆ alkoxy and C ₁ to about C ₆ thioalkyl do. However, R ² is a double bond oxygen only when Z is either -N (R ³ )-or -N (NHR ³ )-. In one embodiment, R ² is hydrogen. In one embodiment, R ² is double bond oxygen.

In one embodiment, R ¹ and R ² together form a fused 6-membered heterocyclic ring.

R ³ is selected from hydrogen, hydroxy, C ₁ to about C ₆ alkyl, C ₂ to about C ₆ alkene or alkane, C ₁ to about C ₆ alkoxy and C ₁ to about C ₆ thioalkyl . In one embodiment, Z is -C (COR ³ )-and R ³ is selected from hydrogen and hydroxy; Preferred is hydroxy to form the carboxylic acid moiety. This carboxylic acid moiety is a potential point of formation of biohydrolyzable esters, aminoacyls and amides with pharmaceutically acceptable salts of the compounds of the invention as described herein. Compounds with any such variation at the R ³ position are included in the present invention. In one embodiment, Z is -N (R ³ )-and R ³ is hydroxy. In one embodiment, Z is -N (NHR ³ )-and R ³ is selected from hydrogen, hydroxy and alkyl of C ₁ to about C ₆ .

In one embodiment, R ² and R ³ together form a fused 6-membered heterocyclic ring.

R ⁵ is selected from hydrogen, hydroxy, amino, halo, C ₁ to about C ₆ alkyl, C ₂ to about C ₄ alkene or alkane and C ₁ to about C ₄ alkoxy. All such alkyl, alkene, alkane and alkoxy moieties are unsubstituted or substituted with 1 to 3 fluoro. In one embodiment, R ⁵ is selected from C ₁ to about C ₂ alkyl, preferably C ₁ alkyl. In one embodiment, R ⁵ is C ₂ alkene. In one embodiment, R ⁵ is C ₁ to about C ₂ alkoxy. In one embodiment, R ⁵ is amino. All R ⁵ C ₁ alkyl, C ₂ alkenes and alkoxy moieties of C ₁ to about C ₂ are unsubstituted or substituted with fluoro moieties. In one embodiment, R ⁵ is selected from hydrogen, hydroxy, chloro, bromo, amino, methyl, monofluoromethyl, difluoromethyl and trifluoromethyl. In one embodiment, R ⁵ is selected from hydrogen, hydroxy, amino and methyl. In one embodiment, R ⁵ is hydrogen.

R ⁶ is hydroxy, aminocarbonyl, fluoro, chloro, bromo, cyano, C ₁ to about C ₂ Alkyl and C ₂ to about C ₄ alkenyl or alkynyl. All such alkyl, alkenyl and alkynyl moieties are unsubstituted or substituted with from 1 to about 3 fluoro. In one embodiment, R ⁶ is selected from hydroxy, fluoro, chloro, bromo and methyl. In one embodiment, R ⁶ is selected from fluoro and chloro. In one embodiment, R ⁶ is fluoro. In one embodiment, R ⁶ is hydroxy. In one embodiment, R ⁶ is methyl.

R ⁷ and R ^{7 '} are each independently hydrogen, C ₁ to about C ₆ alkyl, C ₂ to about C ₆ alkene or alkane, C ₁ to about C ₆ alkoxy, C ₁ to about C ₆ alkyl Thio and C ₁ to about C ₆ heteroalkyl; Provided that both R ⁷ and R ^{7 ′} are not hydrogen; R ⁷ and R ^{7 ′} combine to form a C ₃ to about C ₆ cycloalkyl or heterocyclic ring containing the carbon atom to which they are attached. All such alkyl, alkene, alkane, alkoxy, alkylthio, heteroalkyl, cycloalkyl and heterocyclic moieties are unsubstituted or substituted with 1 to 3 fluoro. In one embodiment, R ⁷ and R ^{7 ′} combine to form a cycloalkyl of C ₃ to about C ₆ . In one embodiment, R ⁷ and R ^{7 ′} combine to form cyclopropyl. In one embodiment, R ⁷ and R ^{7 ′} are selected from C ₁ to about C ₃ alkyl or C ₁ to about C ₃ alkyloxy. In one embodiment, R ⁷ is hydrogen and R ^{7 ′} is selected from hydrogen, C ₁ to about C ₃ alkyl and C ₁ to about C ₃ alkyloxy; Provided that both R ⁷ and R ^{7 ′} are not hydrogen. In one embodiment, R ^{7 ′} is hydrogen and R ⁷ is selected from methoxy, thiomethoxy, methyl and ethyl, all such methoxy, thiomethoxy, methyl and ethyl moieties being unsubstituted or from 1 to about Substituted with three fluoro. In one embodiment, R ^{7 '} is hydrogen and R ⁷ is selected from methyl and ethyl. In one embodiment, R ^{7 ′} is hydrogen and R ⁷ is C ₁ to about C ₆ alkyl, C ₂ to about C ₆ alkene or alkane, C ₁ to about C ₆ alkoxy, C ₁ to about is selected from heteroalkyl, R ⁷ is the carbon atom piperidine ring member which is attached a C ₆ alkylthio and C ₁ to about C ₆ of the will of the S- configuration. In one embodiment, R ^{7 ′} is hydrogen and R ⁷ is methyl and the carbon atom piperidine ring member to which R ⁷ is attached is S-coordinated.

R ⁹ and R ^{9 ′} are each independently selected from hydrogen and alkyl of C ₁ to about C ₃ , or R ⁹ and R ^{9 ′} are heterobetween C ₃ to about C ₆ containing a nitrogen atom to which they are bonded Form a click ring. In one embodiment, R ⁹ and R ⁹ are each independently selected from hydrogen, methyl and ethyl. In one embodiment, R ⁹ and R ⁹ combine to form a C ₃ heterocyclic ring. In one embodiment, R ⁹ and R ^{9 '} are each independently selected from hydrogen and methyl. In one embodiment, R ⁹ and R ^{9 '} are each hydrogen. In one embodiment, each of R ⁹ and R ^{9 '} is each independently selected from hydrogen and methyl, and the carbon atom piperidine ring member to which -NR ⁹ R ^9' is attached is of the S-configuration. In one embodiment, R ⁹ and R ^{9 '} are both hydrogen and the carbon atom piperidine ring member to which -NR ⁹ R ^9' is attached is S-coordinated.

R ¹⁰ represents a portion on a piperidine ring other than R ⁷ , R ^{7 ′} and —NR ⁹ R ^{9 ′} , wherein each R ¹⁰ is independently hydrogen, C ₁ to about C ₆ alkyl, C ₂ to Selected from about C ₆ alkene or alkane, C ₁ to about C ₆ alkoxy and C ₃ -C ₆ cycloalkyl, all such alkyl, alkene, alkane, alkoxy and cycloalkyl moieties being unsubstituted or 1-3 Is substituted with fluoro. In one embodiment, each R ¹⁰ is selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl and methoxy. In one embodiment, each R ¹⁰ is selected from hydrogen, methyl and ethyl. In one embodiment, each R ¹⁰ is hydrogen. In one embodiment, the carbon atom piperidine ring member to which R ¹⁰ is attached is of the S-configuration.

As used herein, any radical is independently selected each time it is used (eg, R ¹ and R ⁵ need not all be the same each time they appear in the definition of a given compound of the invention). .

The compounds of the present invention may comprise chiral center (s), such that any such compound may be in its purified or substantially purified form, the respective optical isomers, diastereomers or enantiomers, and racemic mixtures thereof. And mixtures thereof including these are contemplated.

The following exemplary compounds are prepared using the procedures described herein and their modifications which are within the scope of practice of the skilled person. The following examples are not intended to limit the invention but rather to exemplify some of the embodiments of the invention.

In one embodiment, the present invention provides that X is -C-, Y is -N (R ¹ )-, Z is -C (COR ¹ )-, a is a double bond, b is a single bond, c is a double bond and R ⁹ and ^{9 '} are both hydrogen. In this aspect, the compound has a structure according to formula II:

(II)

Wherein A ¹ , R ¹ , R ² , R ³ , R ⁵ , R ⁶ , R ⁷ , R ^{7 ′} and R ¹⁰ are as defined for Formula (I). In one embodiment, the compound is a compound of Formula II, wherein A ¹ is -C (R ⁸ )-. In one embodiment, the compound of formula (II) is a compound in which R ⁸ and R ¹ do not bond to form a ring.

In another aspect, the invention provides that X is -N-, A ¹ is -C (R ⁸ )-, Y is -C (R ¹ )-, Z is -C (COR ³ )-and a Is a single bond, b is a double bond, c is a double bond, and R ⁹ and R ⁹ are both hydrogen. In this aspect, the compound has a structure according to formula III:

(III)

Wherein R ¹ , R ² , R ³ , R ⁵ , R ⁶ , R ⁷ , R ^{7 ′} and R ¹⁰ are as defined for Formula (I). In one embodiment, the compound of Formula (III) is a compound wherein R ⁸ and R ¹ bind to not form a ring.

In another aspect, the invention provides that X is -C-, A ¹ is -C (R ⁸ )-, Y is -N (R ¹ )-, R ² is double bond oxygen, a is double bond , B is a single bond, c is a single bond, and R ⁹ and R ⁹ are both hydrogen. In this embodiment, the compound has a structure according to formula IV:

Wherein Z, R ¹ , R ⁵ , R ⁶ , R ⁷ , R ^{7 ′} , R ⁸ and R ¹⁰ are as defined for Formula (I).

The compounds of the present invention are also useful precursors of compounds of the formula Q-L-B, wherein Q is a compound of formula (I), L is a binding moiety, and B is a lactam-containing moiety. Wherein the formula is an optical isomer, diastereomer or enantiomer thereof; Pharmaceutically acceptable salts, hydrates, or biohydrolyzable esters, amides and imides thereof. Such compounds and their use are disclosed in US Pat. No. 5,180,719, issued Jan. 19, 1993; US Patent No. 5,387,748, issued February 7, 1995; US Patent No. 5,491,139, issued February 13, 1996; US Patent No. 5,530,116, issued June 25, 1996; And European Patent Publication No. 366,189 published on 2 May 1990 and 366,640 published on 2 May 1990, all of which are incorporated herein by reference. In the compositions and methods of use, the compounds of formula Q-L-B are useful in the same manner as the compounds of formula (I). Thus, they can be interchanged with each other in the composition embodiments of the present invention.

The biological activity of the compounds of the present invention can be compared with ciprofloxacin and other known antimicrobial quinolone compounds. The compounds of the present invention provide better antimicrobial activity against certain quinolone resistant bacteria as compared to ciprofloxacin and certain other prior art compounds. Quinolone-resistant bacteria, for example S. S. aureus, S. saprophyticus, E. E. faecalis, S. S. pyogenes, S. Neumoniae, S. S. viridans, E. E. coli, p. P. aeruginosa, blood. P. mirabilis, K. New Monia K. pneumoniae), two. When tested against E. cloacae, it was found that the MIC value (g / mL) of certain compounds of the invention is lower than ciprofloxacin.

The clastogenecity profile of the compounds of the present invention can be compared with glatifloxacin. Certain compounds of the present invention provide better clastogenecity profiles as compared to glatifloxacin and other prior art compounds. Suitable clastogeneity assays are described in V. Cigvarino, M. J. Suto, J. C. Thiess, Mutation Research, Vol. 298, p. 227 (1993).

III. General reaction methods in the preparation of compounds:

In the preparation of the compounds of the present invention, the order of the synthetic steps can be changed to increase the yield of the desired product. The skilled person will also recognize that a wise choice of reactants, solvents and temperatures is an important factor in successful synthesis. Determination of optimal conditions and the like is common, but it should be understood that various compounds can be produced in a similar manner using the guidance of the following methods. Specific synthesis examples for the various compounds are shown in Section VI.

Starting materials used in the preparation of the compounds of the invention are known or prepared by known methods or are commercially available as starting materials.

It is recognized that one skilled in the art of organic chemistry can readily carry out standard manipulations of organic compounds without further guidance; That is, it is well within the scope and practice of the skilled person. This includes, but is not limited to, reduction of carbonyl compounds to their corresponding alcohols, oxidation, acylation, electrophilic and nucleophilic aromatic substitutions, etherifications, esterifications, saponifications, and the like. Examples of such manipulations are described in standard textbooks, such as March, Advanced Organic Chemistry (Wiley), Carey and Sundberg, Advanced Organic Chemistry (Vol. 2), Fieser & Feiser, Reagents for Organic Synthesis ( 16 volumes), L. Paquette, Encyclopedia of Reagents for Organic Synthesis (8 volumes), and Frost & Fleming, Comprehensive Organic Synthesis (9 volumes).

Those skilled in the art will readily appreciate that by shielding or protecting other functional groups in the molecule, any undesirable side reactions can be avoided and / or the yield of reactions increased so that a particular reaction can best be carried out. Often the skilled person uses protecting groups to increase this yield or to avoid undesirable reactions. Such reactions are found in the literature and are well within the scope of the skilled person. Many examples of such manipulations are described, for example, in T. Greene, Protecting Groups in Organic Synthesis. Of course, amino acids used as starting materials containing reactive side chains are preferably blocked in order to prevent undesirable side reactions.

General procedures for the preparation of quinolone moieties useful in the preparation of compounds of the present invention are described in the following references, all of which are incorporated herein by reference (including the articles listed in these references): Progress in Drug Research, Vol. 21, pp. 9-104 (1977); J. Med. Chem., Vol. 23, pp. 1358-1363 (1980); J. Med. Chem., Vol. 29, pp. 2363-2369 (1986); J. Med. Chem., Vol. 31, p. 503 (1988); J. Med. Chem., Vol. 31, pp. 503-506 (1988); J. Med. Chem., Vol. 31, pp. 983-991 (1988); J. Med. Chem., Vol. 31, pp. 991-1001 (1988); J. Med. Chem., Vol. 31, pp. 1586-1590 (1988); J. Med. Chem., Vol. 31, pp. 1598-1611 (1988); J. Med. Chem., Vol. 32, pp. 537-542 (1989); J. Med. Chem., Vol. 32, p. 1313 (1989); J. Med. Chem., Vol. 32, pp. 1313-1318 (1989); Drugs Exptl. Clin. Res., Vol. 14, pp. 379-383 (1988); J. Pharm. Sci., Vol. 78, pp. 585-588 (1989); J. Het. Chem., Vol. 24, pp. 181-185 (1987); J. Het. Chem., Vol. 25, pp. 479-485 (1988); Chem. Pharm. Bull., Vol. 35, pp. 2281-2285 (1987); Chem. Pharm. Bull., Vol. 36, pp. 1223-1228 (1988); US Patent No. 4,594,347 (June 10, 1986); U.S. Patent 4,599,334 (July 8, 1986); US Patent No. 4,687,770 (August 1, 1987); U.S. Patent 4,689,325 (August 25, 1987); US Patent No. 4,767,762 (August 30, 1988); US Patent No. 4,771,055 (September 13, 1988); US Patent No. 4,795,751 (January 3, 1989); U.S. Patent 4,822,801 (April 18, 1989); U.S. Patent 4,839,355 (June 13, 1989); US Patent No. 4,851,418 (July 25, 1989); US Patent No. 4,886,810 (December 12, 1989); US Patent No. 4,920,120 (April 24, 1990); U.S. Patent 4,923,879 (May 8, 1990); US Patent No. 4,954,507 (September 4, 1990); US Patent No. 4,956,465 (September 11, 1990); US Patent 4,977,154 (December 11, 1990); US Patent No. 4,980,470 (December 25, 1990); U.S. Patent 5,013,841 (May 7, 1991); U.S. Patent 5,045,549 (September 3, 1991); U.S. Patent 5,290,934 (March 1, 1994); US Patent No. 5,328,908 (July 12, 1994); U.S. Patent 5,430,152 (July 4, 1995); European Patent Publication No. 172,651 (February 26, 1986); European Patent Publication No. 230,053 (July 29, 1987); European Patent Publication No. 230,946 (August 5, 1987); European Patent Publication No. 247,464 (December 2, 1987); European Patent Publication No. 284,935 (October 5, 1988); European Patent Publication No. 309,789 (April 5, 1989); European Patent Publication No. 332,033 (September 13, 1989); European Patent Publication No. 342,649 (November 23, 1989); And Japanese Patent Publication No. 09 / 67,304 (1997).

Suitable methods for preparing the quinazoline-2-4-dione compounds of the present invention are described in International Patent Publication No. 01/53273 A1.

The quinolone compounds of the present invention can be prepared in several ways. The versatile method of providing a compound of the present invention is shown in Method I below:

Methods of providing compounds of the invention wherein X is -N- and Y is -C (R ¹ )-are shown in Method II below:

IV. Composition:

The composition of the present invention contains (a) a safe and effective amount of a compound of the present invention and (b) a pharmaceutically acceptable excipient.

The composition may also optionally contain other antimicrobial or other active agents that may or may not act synergistically with the present invention.

A "safe and effective amount" of quinolones is a balanced amount of ratio of reasonable effects / risks without a host of adverse side effects (e.g., toxic, irritant or allergic reactions) that are more than necessary when used in the manner of the present invention. An amount effective to inhibit microbial growth at the site of infection to be treated. Specific "safe and effective amounts" are desired for the particular disease to be treated, the patient's physical condition, the duration of the treatment, the nature of the concurrent therapy (if any), the specific dosage form to be used, the excipient used, the solubility of quinolone in the excipient, and the composition. It depends on such factors as the dosing regimen.

The composition of the present invention is preferably provided in unit dosage form. As used herein, a "unit dosage form" is a composition of the present invention that contains an amount of quinolone suitable for administration in a single dose to a human or lower animal subject in accordance with lawful medical practice. Such compositions are preferably about 30 mg, more preferably about 50 mg, even more preferably about 100 mg, preferably about 20,000 mg, more preferably about 7,000 mg, even more preferably about 1,000 mg Most preferably up to about 500 mg of quinolone.

The compositions of the present invention may be in any of a variety of forms suitable for (eg) oral, rectal, topical or parenteral administration. Various pharmaceutically acceptable excipients well known in the art can be used depending on the particular route of administration desired. These include solid or liquid fillers, diluents, hydrophilicity imparting materials, surfactants and encapsulating materials. Optional pharmaceutical active substances may be included that do not substantially interfere with the antimicrobial activity of the quinolone. The amount of excipient used with quinolone is sufficient to provide an amount of practical substance for administration per unit dose of quinolone. Techniques and compositions for the preparation of dosage forms useful in the methods of the invention are described in the following references, all of which are incorporated herein by reference: Modern Pharmaceutics, Vol. 7, Chapters 9 and 10 (Banker & Rhodes, editors, 1979); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981); And Ansel, Introduction to Pharmaceutical Dosage Forms 2d Edition (1976).

In particular, pharmaceutically acceptable excipients for systemic administration are sugars, starches, celluloses and derivatives thereof, malt, gelatin, talc, calcium sulfate, vegetable oils, synthetic oils, polyols, alginic acid, phosphate buffered solutions, emulsifiers, isotonic saline, and pyrogenic Contains crude water. Preferred excipients for parenteral administration include propylene glycol, ethyl oleate, pyrrolidone, ethanol and sesame oil. Preferably, the pharmaceutically acceptable excipient in the composition for parenteral administration contains at least about 90% by weight of the total composition.

Injectable dosage forms can also be prepared in a dry or lyophilized form. Such forms may be reconstituted with water or saline, depending on the formulation of the dosage form. Such forms may be packaged in individual or multiple dosage forms for easier handling. When lyophilized or dry dosage forms are used, the reconstituted dosage form is preferably isotonic and physiologically compatible pH.

Various oral dosage forms can be used including solid forms such as tablets, capsules, granules and bulk powders. Such oral forms include a safe and effective amount of quinolone, generally at least about 5%, preferably from about 25% to about 50%. Tablets comprising suitable binders, lubricants, diluents, disintegrants, colorants, flavors, flow inducing agents, and melters may be compressed, tablet micronized, enteric coated, sugar coated, film coated, or multiple compressed. have. Oral liquid dosage forms are suspensions, solutions, suspensions, emulsions and / or aqueous solutions which are reconstituted from non-foamable granules, including suitable solvents, preservatives, emulsifiers, suspending agents, diluents, sweeteners, melters, colorants and flavoring agents. And foamable formulations which are reconstituted from foamable granules, which are well known to the skilled person. Preferred excipients for oral administration include gelatin, propylene glycol, cottonseed oil and sesame oil.

The composition of the present invention may also be administered topically to the subject, ie, by administering the composition directly to or applying the epidermal or epithelial tissue of the subject. Such compositions include, for example, lotions, creams, solutions, gels and solids. Such topical compositions preferably contain a safe and effective amount of quinolone, generally at least about 0.1%, preferably from about 1% to about 5%. Excipients suitable for topical administration preferably remain in place on the skin as a continuous film and withstand removal by immersion in sweat or water. Generally, excipients are organic in nature and the quinolone may be dispersed or dissolved in the excipient. Excipients may include pharmaceutically acceptable emollients, emulsifiers, thickeners, solvents and the like, which are well known to those skilled in the art.

V. Methods of Use of the Compounds:

The present invention also provides a method of treating their infectious disease by administering a safe and effective amount of quinolone to a human or other animal subject. As used herein, an "infectious disease" is any disease characterized by the presence of a microbial infection. Preferred methods of the invention are methods for the treatment of bacterial infections. Such infectious diseases include (for example) central nervous system infection, ear infections, middle ear infections (eg acute otitis media), cranial sinus infections, eye infections, oral infections (eg teeth, gingiva and mucous membranes). Infections), upper respiratory tract infections, lower respiratory tract infections including pneumonia, urogenital infections, gastrointestinal infections, gynecological infections, bacteremia, sepsis, peritonitis, bone and joint infections, skin and skin structure infections, bacterial endocarditis, burns, surgical Antimicrobial prophylaxis, and antimicrobial prophylaxis in postoperative patients or immunosuppressive patients (eg, patients undergoing cancer chemotherapy or organ transplant patients).

The term "treatment" is used herein to mean that the administration of a compound of the present invention alleviates a disease associated with an infectious disease in at least a host, preferably a mammalian subject, more preferably a human. Thus, the term “treatment” includes: infectious disease occurring in the host, particularly preventing the host from acquiring the disease if it is easy to acquire but not yet diagnosed, and inhibiting the infectious disease. And / or alleviate or reverse infectious disease. It should be understood that the term "preventing" does not require that the disease state be completely thwarted as long as the method of the present invention relates to the prevention of an infectious disease. (See Webster's Ninth Collegiate Dictionary). Rather, the term prophylactic, as used herein, refers to the ability of the skilled person to identify a population susceptible to an infectious disease such that administration of a compound of the invention can occur prior to the onset of infection. This term does not mean that the disease state is completely avoided.

Quinolone derivatives and compositions of the invention can be administered topically or systemically. Systemic application includes any method of introducing quinolone into body tissue, such as intradural, epidural, intramuscular, transdermal, intravenous, intraperitoneal, subcutaneous, sublingual, rectal, and oral administration. The specific dosage form of the antimicrobial to be administered and the duration of treatment are interdependent. Dosage forms and treatment regimens also include the specific quinolone used, the pattern of resistance of the infecting organism to the quinolone used, the ability of the quinolone to reach the minimum inhibitory concentration at the site of infection, the nature and extent of the other infection (if any), the individual's personality of the subject. It depends on factors such as attributes (eg, body weight), compliance with the treatment regimen, age and health condition of the patient, and the presence and severity of any treatment side effects.

Generally, about 75 mg, more preferably about 200 mg, most preferably about 500 mg to about 30,000 mg, more preferably about 10,000 mg, most preferably in adults (approximately 70 kilograms in weight) Up to about 3,500 mg of quinolone. The duration of the treatment regimen is about 1 day, preferably from about 3 days to about 56 days, preferably about 20 days. Prophylactic therapy (eg, avoidance of opportunistic infections in patients with weakened immunity) can be extended for more than six months depending on legitimate medical practice.

Preferred parenteral administration is via intravenous injection. As is known and done in the art, all formulations for parenteral administration must be sterile. In mammals, especially humans (assuming that the body weight is approximately 70 kilograms), it is acceptable for the individual doses to be about 100 mg, preferably about 500 mg to about 7,000 mg, more preferably about 3,500 mg.

In some cases, for example in general systemic infections or in patients with weakened immunity, the invention may be administered intravenously. Dosage forms are generally isotonic at physiological pH. Dosage depends on the severity of the patient and illness and other parameters generally considered. Determination of such doses is within the scope of the skilled practitioner using the guidance given herein.

Preferred systemic administration is oral administration. The individual dose is about 20 mg, more preferably about 100 mg to about 2,500 mg, more preferably about 500 mg.

Topical administration may be used for systemic delivery of quinolone or for treatment of local infection. The amount of quinolone to be administered topically is dependent on skin sensitivity, the type and location of tissue to be treated, the composition and excipients to be administered (if any), the particular quinolone to be administered, the particular disease to be treated and systemic effects (distinguish from local). Depends on factors such as degree.

VI. Example-Preparation of Compound

a. Precursor Preparation-Nucleus:

3-methoxy-2,4,5-trifluorobenzoyl chloride

3-methoxy-2,4,5-difluorobenzoic acid (43.9 g, 213 mmol) was dissolved in dichloromethane (30 mL) and oxalyl chloride (25 mL, 287 mmol) followed by 4 drops. Dry DMF is added. The mixture is stirred at rt for 6 h and the solvent is removed by evaporation to afford the desired product.

Ethyl 3-methoxy-2,4,5-trifluoro-benzoyl acetate

Monoethyl malonate (26.4 g, 200 mmol) is dissolved in THF (700 mL). Cool this solution at −50 ° C. and add n-butyllithium (160 mL 2.5 M, 400 mmol) keeping the temperature below −50 ° C. The temperature is initially raised to 0 ° C. and cooled to −50 ° C. again. 3-methoxy-2,4,5-trifluorobenzoyl chloride (20.6 g, 92 mmol) is added while maintaining the temperature at -50 ° C and the reaction mixture is then warmed to room temperature. Hydrochloric acid is added to make the pH acidic. The organic phase is washed with sodium bicarbonate and dried and the solvent is evaporated to give the desired product.

Ethyl 3-cyclopropylamino-2- (3-methoxy-2,4,5-trifluoro-benzoyl) acrylate

To a mixture of acetic anhydride (50 mL, 530 mmol) and triethyl orthoformate (50 mL, 300 mmol) ethyl 3-methoxy-2,4,5-trifluoro-benzoyl acetate (52.94 g, 192 mmol) Add. The mixture is refluxed for 2 hours and then cooled to room temperature. Excess reagent is removed by evaporation to give a thick oil which is dissolved in ethanol (150 mL). Then cyclopropylamine (17.2 g, 301 mmol) is added while maintaining the temperature at about 20 ° C. The desired product is isolated by filtration and air dried.

Ethyl 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-quinoline-3-carboxylate

Ethyl 3-cyclopropylamino-2- (3-methoxy-2,4,5-trifluoro-benzoyl) acrylate (30.3 g, 88 mmol) is dissolved in THF. 60% sodium hydride (4.1 g, 103 mmol) in oil is added portionwise while maintaining the temperature below 40 ° C. The solution is stirred at room temperature for 2 hours and then poured into water. The desired product is isolated by filtration and air dried.

1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-quinoline-3-carboxylic acid (precursor A)

Ethyl-1-cyclopropyl-1,4-dihydro-6,7-difluoro-8-methoxy-4-oxo-quinoline-3-carboxylate (28.6 g, 88 mmol) was diluted with acetic acid, water, Suspension in a mixture of sulfuric acid (8/6/1, 300 mL) and reflux for 2 hours. The reaction mixture is cooled at 0 ° C. and the desired product is collected by filtration.

5-Bromo-3-chloro-2,4-difluorobenzoic acid

To a mixture of acetic acid (100 mL), water (20 mL), and nitric acid (26 mL) was added 3-chloro-2,4-difluorobenzoic acid (4 g, 21 mmol) and bromine (2.2 mL, 43 mmol). Add. Then a solution of silver nitrate (7.0 g 41 mmol) in water (20 mL) is added slowly. After 14 hours at 20 ° C., the precipitate is filtered off and rinsed with ether. The organic phase is washed with sodium bisulfite, water, brine and dried over MgSO ₄ . The absorbent used is removed and the solvent is concentrated to give the desired product.

5-bromo-3-chloro-2,4-difluorobenzoyl chloride

5-Bromo-3-chloro-2,4-difluorobenzoic acid (5.2 g, 19 mmol) is suspended in dichloromethane (30 mL), oxalyl chloride (2.92 g, 23 mmol) and dry DMF (3 Drop). The mixture is stirred at room temperature for 3 hours and the desired compound is isolated after evaporation of the solvent.

Ethyl 5-bromo-3-chloro-2,4-difluoro-benzoyl acetate

Magnesium (0.475 g, 19.5 mmol) is suspended in ethanol (1.5 mL, 26.5 mmol) and carbon tetrachloride (0.16 mL) is added. A solution of diethylmalonate (3 mL, 19.7 mmol) in ethanol (15 mL) is added dropwise and the mixture is stirred at 60 ° C. to ensure complete dissolution of magnesium. The mixture is cooled at -5 ° C and 5-bromo-3-chloro-2,4-difluorobenzoyl chloride (5.5 g, 19.0 mmol) is added dropwise. The mixture is stirred at room temperature for 1 hour. Diethyl ether (50 mL) and water (20 mL) are added and the mixture is acidified with concentrated hydrochloric acid. After separation of the organic phase and removal of the solvent, the residue is suspended in water (40 mL) and PTSA (0.1 g) is added. The suspension is heated under reflux for 2 hours, cooled to room temperature and extracted with diethyl ether. The desired product is obtained after evaporation of the solvent.

Ethyl 3-cyclopropylamino-2- (5-bromo-3-chloro-2,4-difluoro-benzoyl) acrylate

Ethyl 5-bromo-2,4-difluoro-3-chloro-benzoyl acetate (6.2 g, 18 mmol) was added acetic anhydride (4.4 mL, 47 mmol) and triethyl orthoformate (4.5 mL, 27 mmol) In a mixture of and heated to reflux for 2 hours. The volatiles are evaporated, the residue is dissolved in ethanol (20 mL) and the resulting solution is cooled at 0 ° C. Cyclopropylamine (2 mL, 29 mmol) is added and after 30 minutes the desired product is isolated by filtration and air dried.

Ethyl 6-Bromo-8-chloro-1-cyclopropyl-1,4-dihydro-7-fluoro-4-oxo-quinoline-3-carboxylate

Ethyl 3-cyclopropylamino-2- (5-bromo-2,4-difluoro-3-chloro-benzoyl) acrylate (2.95 g, 7 mmol) was dissolved in THF (15 mL) and 60% hydrogenated. Sodium (0.29 g, 7 mmol) is added in portions. After 1 hour at room temperature the suspension is poured into water (100 mL) and the desired product is isolated by filtration and air dried.

6-Bromo-8-chloro-1-cyclopropyl-1,4-dihydro-7-fluoro-4-oxoquinoline-3-carboxylic acid (precursor B)

Ethyl 6-bromo-1-cyclopropyl-1,4-dihydro-7-fluoro-8-chloro-4-oxo-quinoline-3-carboxylate (1.9 g, 5 mmol) was added acetic acid, water, Suspension in a mixture of sulfuric acid (8/6/1, 30 mL) and reflux for 2 hours. The reaction mixture is cooled to room temperature and poured into cold water (50 mL). The precipitate is collected by filtration, washed with water and air dried.

Ethyl 8-chloro-1-cyclopropyl-1,4-dihydro-7-fluoro-6-methyl-4-oxoquinoline-3-carboxylate

Ethyl 6-bromo-8-chloro-1-cyclopropyl-7-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (0.5 g, 1.3 mmol), lithium chloride (0.165 g , 3.9 mmol), tris (dibenzylideneacetone) dipalladium (0.120 g, 0.13 mmol), tetramethyltin (0.465 g, 2.6 mmol) and 2,6-di-tert-butyl-4-methyl-phenol ( BHT, 25 mg) is combined in DMF (40 mL) and heated at 70-75 ° C. for 18 hours. The solvent is then removed in vacuo. The residue is triturated with hexanes and then purified by flash chromatography on silica gel using 1% methanol in chloroform to give the desired product.

8-Chloro-1-cyclopropyl-1,4-dihydro-7-fluoro-6-methyl-4-oxoquinoline-3-carboxylic acid (precursor C)

Ethyl 8-chloro-1-cyclopropyl-1,4-dihydro-7-fluoro-6-methyl-4-oxo-quinoline-3-carboxylate (0.290 g, 0.9 mmol) was added to acetic acid, water and sulfuric acid. In a mixture of (8/6/1, 3 mL) and refluxed for 2 h. The reaction mixture is cooled to room temperature and poured into cold water (5 mL). The precipitate is collected by filtration, washed with water and air dried.

3-chloro-2,4-difluoro-bromobenzene

To a solution of diisopropylamine (19 mL, 135 mmol) in THF (125 mL) cooled to -20 ° C is added n-butyllithium (80 mL, 1.6 M in hexanes, 128 mmol). The temperature is raised to 0 ° C. for 5 minutes and reduced to −78 ° C. 2,4-Difluoro-bromobenzene (25 g, 130 mmol) is then added and the reaction mixture is stirred at -65 ° C for 2 hours. Hexachloroacetone (25 mL, 164 mmol) is added and the solution is allowed to warm to room temperature. After evaporation of the solvent the residue is distilled under vacuum to afford the desired product.

3-Chloro-2,4-difluorobenzoic acid

To a solution of 3-chloro-2.4-difluoro-bromobenzene (21.5 g, 94.5 mmol) in ether (220 mL) at −78 ° C. n-butyllithium (59 mL, in Et ₂ O (60 mL) A mixture of 1.6 M in hexanes, 94.4 mmol) is added while maintaining the temperature below -70 ° C. After 15 minutes, CO ₂ is bubbled into the reaction mixture while maintaining the temperature below -70 ° C. After warming to room temperature, water and hydrochloric acid are added and the organic phase is separated and dried. The solvent is removed to give the desired product.

5-Nitro-3-chloro-2,4-difluorobenzoic acid

3-chloro-2,4-difluorobenzoic acid (10 g, 52 mmol) is added to a mixture of fuming nitric acid (10 mL) and sulfuric acid (13 mL) at 0 ° C. The suspension is then stirred for 30 minutes at room temperature and poured over ice. The resulting solid is filtered to give the desired product.

5-nitro-3-chloro-2,4-difluorobenzoyl chloride

5-nitro-3-chloro-2,4-difluorobenzoic acid (6.94 g, 29 mmol) and oxalyl chloride (4.06 g, 32 mmol) were dissolved in dichloromethane (30 mL), followed by DMF 4 drop. Add. The reaction mixture is stirred for 14 hours at room temperature and the solvent is evaporated under reduced pressure to afford the desired product.

Ethyl 5-nitro-3-chloro-2,4-difluoro-benzoyl acetate

Monoethyl malonate (3.26 g, 24.7 mmol) is dissolved in THF (10 mL) and the solution is cooled at -50 ° C. n-butyllithium (30 mL, 1.6 M, 48 mmol) is added over 30 minutes. A solution of 5-nitro-3-chloro-2,4-difluorobenzoyl chloride (3.35 g, 13 mmol) in THF (2 mL) is added keeping the temperature below -50 ° C. The reaction mixture is then stirred at rt for 3 h and 1N HCl (5 mL) is added. The organic layer is separated and the aqueous phase is extracted with ethyl acetate. The combined organic phases are dried and the crude product is obtained after evaporation of the solvent. Pure product is obtained after flash chromatography using 5% EtOAc in CH ₂ Cl ₂ .

Ethyl 3-cyclopropylamino-2- (2,4-difluoro-3-chloro-5-nitro-benzoyl) acrylate

Ethyl 5-nitro-3-chloro-2,4-difluoro-benzoyl acetate (4.10 g, 13.3 mmol) was dissolved in triethyl orthoformate (3.4 mL, 20 mmol) and acetic anhydride (6 mL, 64 mmol). Dissolve in the mixture. The reaction mixture is warmed at 120 ° C. for 3 hours and the remaining volatiles are removed in vacuo. The residue is dissolved in ethanol (15 mL) and the solution is cooled at -5 ° C. Cyclopropylamine (0.88 mL, 12.7 mmol) is added and the desired product is isolated by filtration and air dried.

Ethyl 1-cyclopropyl-1,4-dihydro-7-fluoro-8-chloro-6-nitro-4-oxo-quinoline-3-carboxylate (precursor D)

At 0 ° C. ethyl 3-cyclopropylamino-2- (2,4-difluoro-3-chloro-5-nitro-benzoyl) acrylate (3.41 g, 9.1 mmol) is dissolved in EtOAc (40 mL). Potassium carbonate (3.9 g, 28 mmol) is added and the reaction mixture is stirred at 0 ° C. for 2 hours. The mixture is poured into ice water and the desired product is isolated by filtration, washed with water and air dried.

2,6-dichloro-5-fluoro-3-nicotinoyl chloride

2,6-Dichloro-5-fluoro-3-nicotinic acid (4 g, 19 mmol) is suspended in CH ₂ Cl ₂ and oxalyl chloride (2.72 g, 21 mmol) is added followed by 3 drops of DMF. The mixture is stirred at room temperature for 3 hours and the solvent is evaporated to yield the desired product.

Ethyl-3- (2,6-dichloro-5-fluoropyridinyl) -3-oxo-2-carboxyethyl propanoate

Magnesium turnings (0.44 g, 18 mmol) are added to a mixture of ethanol (1.5 mL, 26 mmol) and carbon tetrachloride (0.15 mL), and diethyl malonate (2.76 mL, 18 mmol) is added over 15 minutes. do. The temperature is kept at 50 ° C. for 2 hours and then cooled at 0 ° C. 2,6-Dichloro-5-fluoro-3-nicotinoyl chloride (4.3 g, 19 mmol) is added gradually while maintaining the temperature below 5 ° C. After 1 hour at room temperature, the mixture is acidified, diluted with water and extracted with toluene. The solvent is evaporated to give the desired product.

Ethyl-3- (2,6-dichloro-5-fluoropyridinyl) -3-oxo-propanoate

Ethyl-3- (2,6-dichloro-5-fluoropyridinyl) -3-oxo-2-carboxyethyl propanoate (6 g, 17 mmol) was added water (30 mL) and p-toluenesulfonic acid. Mix with monohydrate (0.15 g, 0.8 mmol) and heat at 100 ° C. for 1 hour. After cooling to room temperature, the aqueous solution is extracted with ethyl acetate and the combined organic layers are dried over Na ₂ SO ₄ . The absorbent used is removed by filtration and the filtrate is concentrated to give the desired product.

Ethyl-3- (2,6-dichloro-5-fluoropyridinyl) -3-oxo-2-ethoxymethylene-propanoate

Ethyl-3- (2,6-dichloro-5-fluoropyridinyl) -3-oxo-propanoate (5 g, 18 mmol) was added triethyl orthoformate (4.3 mL, 26 mmol) and acetic anhydride. (4.1 mL, 43 mmol) and this mixture is heated under reflux for 2 h. The mixture is then concentrated in vacuo to afford the desired product.

Ethyl-3- (2,6-dichloro-5-fluoropyridinyl) -3-oxo-2-cyclopropylaminomethylene-propanoate

Ethyl-3- (2,6-dichloro-5-fluoropyridinyl) -3-oxo-2-ethoxymethylene-propanoate (2.65 g, 8 mmol) was dissolved in ethanol (5 mL), The solution is cooled at 0 ° C. Cyclopropylamine (0.8 mL, 12 mmol) is added gradually and the mixture is stirred at rt for 1 h. After evaporation of the volatiles the desired product is obtained.

Ethyl-7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-naphthyridine-3-carboxylate (precursor E)

Dissolve ethyl-3- (2,6-dichloro-5-fluoropyridinyl) -3-oxo-2-cyclopropylaminomethylene-propanoate (1.09 g, 3 mmol) in acetonitrile (15 mL) And potassium carbonate (840 mg, 6 mmol) is added. The mixture is heated under reflux for 18 hours and poured into water. The precipitate is filtered off and purified by flash chromatography using 2% methanol in CH ₂ CL ₂ .

Ethyl-3- (2,3,4,5-tetrafluorophenyl) -3-oxo-propanoate

Ethyl hydrogen malonate (26.4 g, 200 mmol) is dissolved in THF (700 mL) and the solution is cooled at -35 ° C. n-BuLi (160 mL, 2.5 M in hexanes, 400 mmol) is added dropwise and the solution is cooled at -58 ° C. A solution of 2,3,4,5-tetrafluorobenzoyl chloride (21.1 g, 100 mmol) in THF (10 mL) is added and the reaction is allowed to warm to room temperature. Pour this solution into 1N HCl and extract with ether. The extract is washed with bicarbonate solution, brine and dried over Na ₂ SO ₄ . The desired product is purified by flash chromatography on silica gel using 15% EtOAc in hexanes.

Ethyl-3- (2,3,4,5-tetrafluorophenyl) -3-oxo-2- [3-amino-2S-methyl-propanol-3-yl] -methylene-propanoate

Ethyl-3- (2,3,4,5-tetrafluorophenyl) -3-oxo-propanoate (10 g. 38 mmol) was added triethyl orthoformate (10 mL, 60 mmol) and acetic anhydride ( 10 mL, 106 mmol), and the solution is heated under reflux for 3 hours. After concentration in vacuo, the residue is dissolved in CH ₂ Cl ₂ and cooled at 0 ° C. 2S-aminopropanol (4.26 g, 55 mmol) is added dropwise and the solution is allowed to warm to room temperature. The product is purified by flash chromatography on silica gel using 25% EtOAc in hexanes.

Ethyl-9,10-difluoro-2,3-dihydro-3S-methyl-7-oxo-7H-pyrido [1,2,3-de] -1,4-benzoxazine-6-carboxyl Rate

Ethyl-3- (2,3,4,5-tetrafluorophenyl) -3-oxo-2- [3-amino-2S-methyl-propanol-3-yl] -methylene-propanoate (9.78 g, 28 mmol) is dissolved in DMF (25 mL) and 60% sodium hydride (1.17 g, 29 mmol) in oil is added. After 20 minutes at room temperature, the solution is heated overnight. The solvent is removed in vacuo and the residue is triturated with hexanes and treated with water. The desired product is obtained by filtration.

9,10-difluoro-2,3-dihydro-3S-methyl-7-oxo-7H-pyrido [1,2,3-de] -1,4-benzoxazine-6-carboxylic acid ( Precursor F)

Ethyl-9,10-difluoro-2,3-dihydro-3S-methyl-7-oxo-7H-pyrido [1,2,3-de] -1,4-benzoxazine-6-carboxyl Rate (8.2 g, 27 mmol) is dissolved in THF and 10% aqueous KOH (25 mL) is added. This solution is heated at 65 ° C. for 2 hours. THF is evaporated and the pH is adjusted to 3 by addition of acetic acid. The desired product is obtained by filtration.

Phenyl N-cyclopropyliminomercaptothioformate

N-cyclopropyl isothiocyanate (5 g, 50 mmol) and thiophenol (5.2 mL, 51 mmol) are mixed together at 0 ° C. After stirring for 30 min at 0 ° C., 2 drops of triethylamine are added to initiate the reaction. The mixture immediately turns yellow and slowly solidifies. The white solid is broken up, collected on a filter and washed with hexane to give the desired product.

Phenyl N-cyclopropyliminochlorothioformate

Phosphorus pentachloride (10.5 g, 50 mmol) is added to phenyl N-cyclopropyliminomercaptothioformate, the flask is equipped with a reflux condenser and the solid mixture is heated at 65 ° C. under argon. The solid is slowly melted to a yellow solution. The mixture is stirred at 65 ° C. for 6 hours and then cooled to room temperature. The flask is equipped with a distillation apparatus and the desired product is distilled off.

2,3,4,5,6-pentafluorobenzoyl acetate

Ethyl hydrogen malonate (33.69 g, 255 mmol) is dissolved in dry THF (640 mL). The mixture is cooled to -78 ° C and n-butyllithium (319 mL, 1.6 M in hexanes, 510 mmol) is added dropwise rapidly to maintain the internal temperature below -30 ° C. The cooling bath is then removed and the mixture is warmed to -20 ° C. The reaction is recooled to −78 ° C. and 2,3,4,5,6-pentafluorobenzoyl chloride (25 g, 108 mmol) is added via dry cannula in dry THF (40 mL). The yellow solution is warmed to room temperature and stirred overnight. The reaction mixture is poured into a solution of vigorously stirred dilute HCl (125 mL) and stirred for 1 h, then the layers are separated and the aqueous layer is extracted with ether. The organic phase is washed with saturated aqueous sodium bicarbonate solution and brine and dried over MgSO 4. After concentration, the desired product is distilled off under reduced pressure (5 mm Hg).

Ethyl 1-cyclopropyl-2-phenylthio-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate

2,3,4,5,6-pentafluorobenzoyl acetate (6.02 g, 21 mmol) is dissolved in dry toluene (100 mL). Dry sodium hydride (0.562 g, 23 mmol) is added under argon and the mixture is stirred for 30 minutes. Phenyl N-cyclopropyliminochlorothioformate (6.78 g, 32 mmol) is then added in dry toluene (15 mL). The resulting mixture is heated at 50 ° C. for 4 hours, then at reflux for 20 hours, then cooled to room temperature and diluted with CH ₂ Cl ₂ . The organic layer is washed once with water, dried over MgSO 4 and concentrated to give a dark oil which is purified by flash chromatography on silica gel using 15% acetone in hexanes.

Ethyl 1-cyclopropyl-2-phenylsulfinyl-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate

Ethyl 1-cyclopropyl-2-phenylthio-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (3.38 g, 7.7 mmol) was added to CH ₂ Dissolve in Cl ₂ (100 mL). m-chloroperbenzoic acid (1.9 g, 11 mmol) is added and the solution is stirred overnight at room temperature. The reaction mixture is extracted with sodium bicarbonate, dried over MgSO ₄ and concentrated in vacuo. The desired product is obtained after purification by flash chromatography on silica gel using 15% acetone in hexanes.

5,6,7,8-tetrafluoro-9-cyclopropyl-1,3,4,9-tetrahydroisothiazolo [5,4-b] quinoline-3,4-dione (precursor G)

Ethyl 1-cyclopropyl-2-phenylsulfinyl-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (0.225 g, 0.496 mmol) was THF (15 mL) and cool the solution at 0 ° C. Then sodium hyposulfite (60 mg) dissolved in water (2 mL) is added followed by sodium bicarbonate solution (0.5 g in 10 mL). The solution is stirred at 0 ° C. for 1 h and hydroxylamine-O-sulfonic acid (0.264 g, 2.3 mmol) is added. The solution is allowed to warm to room temperature and treated with dilute hydrochloric acid after 3 hours. The crude desired product is collected by filtration and purified by crystallization from ethanol.

4-tert-butoxy-3-chloro-2,5,6-trifluoropyridine

3-Chloro-2,4,5,6-tetrafluoropyridine (50.0 g, 270 mmol) is dissolved in dry THF (500 mL) and cooled to 0 ° C. A solution of lithium tert-butoxide (270 mL, 1.0 M in THF, 270 mmol) is added dropwise over 50 minutes and then the solution is stirred at 0 ° C. for an additional 90 minutes and then warmed to room temperature. The reaction mixture is poured into hexane (1000 mL) and filtered through a pad of Celite®. After concentration via rotary evaporation, the liquid is purified by flash chromatography on silica gel using hexane to isolate the desired compound.

4-tert-butoxy-2,5,6-trifluoropyridine

Sodium acetate (12.75 g) and 10% Pd / C (18.66 g) were added 4-tert-butoxy-3-chloro-2,5,6-trifluoropyridine (31.03 g, 129 mmol) in THF (800 mL). ) And the mixture is placed under hydrogen (1 atm). The mixture is stirred for 48 hours at room temperature. The catalyst is removed by filtration through a pad of Celite®, which is washed with hexane. After concentration, the residue is purified by flash chromatography on silica gel using 5% Et ₂ O in petroleum ether to isolate the desired compound.

4-tert-butoxy-2,3,6-trifluoro-5-methylpyridine

n-butyllithium (45.6 mL, 2.5 M in hexanes, 114 mmol) was added to a solution of dry diisopropylamine (14.93 mL, 107 mmol) in dry THF (300 mL) via syringe at -78 ° C under argon and The mixture is stirred for 20 minutes. A solution of 4-tert-butoxy-2,5,6-trifluoropyridine (15.58 g, 76 mmol) in dry THF (30 mL) is added. Methyl iodide (9.45 mL, 152 mmol) is added via syringe and the cooling bath is removed. After stirring for 90 minutes, the slurry is poured into saturated aqueous ammonium chloride solution (250 mL) and extracted twice with hexane. The combined organic layers are washed with water and brine and dried over MgSO 4. The solvent is evaporated to give the desired compound.

4-tert-butoxy-2,5-difluoro-6-hydrazino-3-methylpyridine

Hydrazine monohydrate (16.6 mL, 342 mmol) was added to a solution of 4-tert-butoxy-2,3,6-trifluoro-5-methylpyridine (13.19 g, 60 mmol) in n-propanol (200 mL). The resulting solution is heated under reflux for 16 h under argon. The mixture is cooled to room temperature and the solvent is evaporated. The residue is redissolved in CH ₂ Cl ₂ , washed with water and dried over MgSO 4. The desired product is obtained by evaporation of the solvent.

4-tert-butoxy-2,5-difluoro-3-methylpyridine

Crude 4-tert-butoxy-2,5-difluoro-6-hydrazino-3-methylpyridine is dissolved in methanol (150 mL) and 20% aqueous sodium hydroxide solution (32 mL) is added. Air is bubbled through the reaction mixture while the reaction mixture is stirred for 48 hours. The solvent is removed and the residue is redissolved in CH ₂ Cl ₂ . The organic layer is washed once with water, dried over MgSO 4 and the solvent is evaporated. The desired product is purified by flash chromatography on silica gel using 5% Et ₂ O in hexanes.

2- (4-tert-butoxy-5-fluoro-3-methyl-2-pyridinyl) cyclopropaneacetonitrile

Dry diisopropylamine (12.0 mL, 86 mmol) is dissolved in anhydrous THF (80 mL). The solution is cooled at −78 ° C. and n-butyllithium (36.6 mL, 2.5 M in hexanes, 92 mmol) is added. After 30 minutes, cyclopropylacetonitrile (3.6 g, 44 mmol) is added in dry THF (20 mL). Then 4-tert-butoxy-2,5-difluoro-3-methyl-2-pyridine (8.45 g, 42 mmol) in THF (20 mL) is added. The mixture is stirred at −78 ° C. for 1 hour and at room temperature for 1 hour, then it is poured into saturated aqueous ammonium chloride solution (150 mL) and extracted twice with ether. The combined organic layers are washed with brine, dried over MgSO 4 and concentrated to give a yellow oil. This oil is purified by flash chromatography on silica gel using 20% EtOAc in hexanes to afford the desired product.

2- (4-hydroxy-5-fluoro-3-methyl-2-pyridinyl) cyclopropaneacetonitrile

2- (4-tert-butoxy-5-fluoro-3-methyl-2-pyridinyl) cyclopropaneacetonitrile (10.5 g, 40 mmol) was dissolved in pure trifluoroacetic acid (100 mL) and at room temperature Stir for 1 hour. Trifluoroacetic acid is then removed under reduced pressure to give the desired product.

2- (4-chloro-5-fluoro-3-methyl-2-pyridinyl) cyclopropaneacetonitrile

Crude 2- (4-hydroxy-5-fluoro-3-methyl-2-pyridinyl) cyclopropaneacetonitrile is dissolved in CH ₂ Cl ₂ (150 mL), anhydrous DMF (30.9 mL, 399 mmol), Then phosphorus oxychloride (3.7 mL, 40 mmol) is added. The mixture is stirred at rt for 48 h, then poured into cold water (150 mL) and extracted with CH ₂ Cl ₂ . The pH of the aqueous layer is raised to 7 with 1 N NaOH. The aqueous layer is extracted twice more with CH ₂ Cl ₂ and the combined organic layers are washed once with water, dried over MgSO 4 and concentrated. The desired product is purified by flash chromatography on silica gel using 20% EtOAc in hexanes.

Ethyl 2- (4-chloro-5-fluoro-3-methyl-2-pyridinyl) cyclopropaneacetate

Hydrogen chloride gas was bubbled through a solution of 2- (4-chloro-5-fluoro-3-methyl-2-pyridinyl) cyclopropaneacetonitrile (2.91 g, 13 mmol) in ethanol (9 mL) to give weight This 3.56 g increase and then the mixture is heated to boiling. Water (0.32 mL) is added and the mixture is heated at reflux for 2 hours before it is cooled to room temperature and additional water is added. The pH is adjusted to 7 with solid sodium bicarbonate and it is extracted with CH ₂ Cl ₂ . The combined organic layers are washed with water, dried over MgSO 4 and concentrated to give a yellow liquid which is purified by flash chromatography on silica gel using 20% EtOAc in hexanes to give the desired product.

2- (4-chloro-5-fluoro-3-methyl-2-pyridinyl) cyclopropaneethanol

Ethyl 2- (4-chloro-5-fluoro-3-methyl-2-pyridinyl) cyclopropaneacetate (1.31 g, 4.8 mmol) is dissolved in dry THF (10 mL). Lithium aluminum hydride (91.8 mg, 24 mmol) is added to the solution and it is stirred at room temperature for 1 hour. The reaction mixture is quenched with saturated aqueous sodium potassium stannate solution (25 mL) and extracted with ether. The combined organic layers are dried over MgSO 4 and concentrated to give the desired product.

2- (4-chloro-5-fluoro-3-methyl-2-pyridinyl) cyclopropaneacetaldehyde

Of 2- (4-chloro-5-fluoro-3-methyl-2-pyridinyl) -cyclopropanecarboxylic ethanol _{CH 2 Cl 2 (5 mL)} CH 2 Cl 2 (12 mL) at -78 ℃ dissolved in dry To a solution of DMSO (0.82 mL, 11.6 mmol) and oxalyl chloride (0.51 mL, 5.8 mmol) is added. After stirring for 15 minutes, triethylamine (3.31 mL, 23.7 mmol) is added and the mixture is further stirred for 5 minutes at -78 ° C and for 10 minutes at 0 ° C. The reaction mixture is then quenched with water and extracted with CH ₂ Cl ₂ . The combined organic layers are washed with water, dried over MgSO 4 and concentrated to give the desired product.

Diethyl [(4-chloro-5-fluoro-3-methyl-2-pyridinyl) cyclopropanemethylmethylene] -malonate

Piperidine (1.14 mL), acetic acid (1.14 mL) and diethyl malonate (3.80 mL, 25 mmol) were added 2- (4-chloro-5-fluoro-3-methyl-2- in ethanol (40 mL). To the solution of pyridinyl) cyclopropaneacetaldehyde, the reaction mixture is heated under reflux for 4 hours under argon. The solvent is removed and the residue is dissolved in ether. The ether layer is washed with water and brine, dried over MgSO 4 and concentrated. The desired product is purified by flash chromatography on silica gel using EtOAc / hexanes.

Ethyl 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (precursor H)

A solution of diethyl [(4-chloro-5-fluoro-3-methyl-2-pyridinyl) cyclopropanemethyl-methylene] malonate (539.1 mg, 1.5 mmol) in diphenyl ether (25 mL) was heated to 220 ° C. Heated for 45 minutes and then cooled to room temperature. The desired product is purified by flash chromatography on silica gel using hexane and then ethyl acetate as solvent.

2,4,6-trifluoropyridine

Sodium acetate (12.75 g) and 10% Pd / C (18.66 g) were added to a solution of 3,5-dichloro-2,4,6-trifluoropyridine (26 g, 129 mmol) in THF (800 mL). Add and place this mixture under hydrogen (1 atm). The mixture is stirred at rt for 48 h. The catalyst is removed by filtration through a pad of Celite®, which is washed with hexane. After concentration the liquid is purified by flash chromatography on silica gel using 5% ether in hexanes to isolate the desired compound.

3-nitro-2,4,6-trifluoropyridine

At 0 ° C. 2,4,6-trifluoropyridine (16.6 g, 125 mmol) is added to a mixture of 35 ml fuming nitric acid and 45 ml sulfuric acid. The suspension is then stirred for 30 minutes at room temperature and poured over ice. Filtration yields the desired product.

4-tert-butoxy-2,6-difluoro-3-nitro-pyridine

3-nitro-2,4,6-trifluoropyridine (19.6 g, 110 mmol) is dissolved in dry THF (250 mL) and cooled at 0 ° C. A solution of lithium tert-butoxide (135 mL, 1.0 M in THF, 110 mmol) is added dropwise over 50 minutes, then the solution is stirred at 0 ° C. for an additional 90 minutes and then warmed to room temperature. The reaction mixture is poured into hexane (500 mL) and filtered through a pad of Celite®. After concentration via rotary evaporation, the liquid is purified by flash chromatography on silica gel using 5% ether in hexanes to isolate the desired compound.

4-tert-butoxy-2,6-difluoro-3- (trimethylstannyl) -5-nitro-pyridine

To a solution of (tert-butyldimethylsisryl) -tert-butylamine (23 mL, 95.9 mmol) in THF (120 mL) at -78 ° C. under argon n-butyllithium (61.3 mL, 1.5 M in hexane, 91.9 mmol) is added and the solution is warmed to 0 ° C. to give a solution of LiBSBA. In a separate flask, a solution of 4-tert-butoxy-2,4-difluoro-3-nitro-pyridine (17.63 g, 75.9 mmol) in THF (275 mL) was cooled to -78 ° C under argon and Me ₃ SnCl (45.7 mL, 2.5 M in THF, 114.3 mmol) is added. The LiBSBA solution is then added dropwise while keeping the internal temperature below -74 ° C. The resulting solution is stirred at −78 ° C. for 30 minutes and then poured into saturated aqueous ammonium chloride solution (300 mL). The aqueous solution is extracted with hexane (three times) and the combined organic layers are washed with water and brine, dried over MgSO ₄ and concentrated. Purification by flash chromatography using EtOAc / hexanes affords the desired product.

4-tert-butoxy-2,6-difluoro-3-methyl-5-nitro-pyridine

Tris (dibenzylideneacetone) dipalladium (21.1 g, 23.1 mmol), tri-o-tolylphosphine (28.1 g, 91.7 mmol), cuprous chloride (4.55 g, 45.5 mmol) and potassium carbonate (6.35 g , 45.5 mmol) is placed under argon. After addition of DMF (1600 mL), the mixture was stirred at room temperature for 5 minutes and then 4-tert-butoxy-2,6-difluoro-3- (trimethylstannyl)-in DMF (1200 mL)- A solution of 5-nitro-pyridine (17.99 g, 45.5 mmol) and a solution of methyl iodide (228 mL, 0.2 M, 45.5 mmol) in DMF are added sequentially. The resulting mixture is stirred at 50 ° C. for 90 minutes under argon. After cooling to room temperature, the reaction mixture is filtered and concentrated under reduced pressure by azeotropic removal of DMF with toluene. Purify the residue by flash chromatography on silica gel using a mixture of 2: 1, 1: 1 and 2: 3 hexanes and EtOAc as eluent to afford the desired product.

4-tert-butoxy-2-fluoro-6-hydrazino-3-methyl-5-nitro-pyridine

Hydrazine monohydrate (8 mL, 165 mmol) was converted to 4-tert-butoxy-2,6-difluoro-3-methyl-5-nitro-pyridine (8.1 g, 32.8 mmol) in n-propanol (115 mL). Is added and the resulting solution is heated under reflux under argon for 16 h. The mixture is cooled to room temperature and the solvent is evaporated. The residue is redissolved in CH ₂ Cl ₂ , washed with water and dried over MgSO 4. The desired product is obtained by evaporation of the solvent.

4-tert-butoxy-2-fluoro-3-methyl-5-nitro-pyridine

Crude 4-tert-butoxy-2-fluoro-6-hydrazino-3-methyl-5-nitro-pyridine is dissolved in methanol (85 mL) and 20% aqueous sodium hydroxide solution (18 mL) is added. The reaction mixture is stirred for 48 hours while bubbling air through the mixture. The solvent is removed, the residue is redissolved in CH ₂ Cl ₂ and the solution is washed once with water and dried over MgSO 4. The absorbent used is removed by filtration, the solvent is removed and the residue is purified by chromatography on silica gel using 5% ether in hexanes.

2- (4-tert-butoxy-5-nitro-3-methyl-2-pyridinyl) cyclopropaneacetonitrile

Dry diisopropylamine (7.0 mL, 50 mmol) is dissolved in anhydrous THF (45 mL). The solution is cooled to -78 ° C and n-butyllithium (20.8 mL, 2.5 M in hexanes, 52 mmol) is added. After 30 minutes, cyclopropylacetonitrile (2.05 g, 25.2 mmol) is added in dry THF (10 mL). Then 4-tert-butoxy-2-fluoro-3-methyl-5-nitro-pyridine (5.75 g, 25.2 mmol) in THF (10 mL) is added. The mixture is stirred at −78 ° C. for 1 hour and at room temperature for 1 hour, then poured into saturated aqueous ammonium chloride solution (85 mL) and extracted twice with ether. The combined organic layers are washed with brine, dried over MgSO 4 and concentrated to give a yellow oil. This oil is purified by flash chromatography on silica gel using 20% ethyl acetate in hexanes to give the desired product.

2- (4-hydroxy-5-nitro-3-methyl-2-pyridinyl) cyclopropaneacetonitrile

2- (4-tert-butoxy-5-nitro-3-methyl-2-pyridinyl) cyclopropaneacetonitrile (6.0 g, 20.7 mmol) is dissolved in pure trifluoroacetic acid (60 mL) and this mixture Stir at room temperature for 1 hour. Trifluoroacetic acid is then removed by rotary evaporation to afford the desired product.

2- (4-chloro-5-nitro-3-methyl-2-pyridinyl) cyclopropaneacetonitrile

Crude 2- (4-hydroxy-5-nitro-3-methyl-2-pyridinyl) cyclopropaneacetonitrile is dissolved in CH ₂ Cl ₂ (85 mL), followed by anhydrous DMF (17.6 mL, 227 mmol). Phosphorous oxychloride (2.1 mL, 22.5 mmol) is added. The mixture is stirred at rt for 48 h and then poured into cold water (85 mL) and extracted with CH ₂ Cl ₂ . The pH of the aqueous layer is raised to 7 with 1 N NaOH. The aqueous layer is extracted twice more with CH ₂ Cl ₂ and the combined organic layers are washed once with water, dried over MgSO ₄ and concentrated. The desired product is purified by flash chromatography using 20% ethyl acetate in hexanes.

Ethyl 2- (4-chloro-5-nitro-3-methyl-2-pyridinyl) cyclopropaneacetate

Hydrogen chloride gas (2.02 g, 55 mmol) was added to a solution of 2- (4-chloro-5-nitro-3-methyl-2-pyridinyl) cyclopropaneacetonitrile (1.85 g, 7.4 mmol) in ethanol (5 mL). Bubbling through, and the resulting mixture is heated to boiling. Water (0.18 mL) is added and heating continued for 2 hours under reflux, then the mixture is cooled to room temperature and water is added. The pH is adjusted to 7 with solid sodium bicarbonate and the aqueous solution is extracted with CH ₂ Cl ₂ . The combined organic layers are washed with water, dried over MgSO ₄ and concentrated to give a yellow liquid which is purified by flash chromatography on silica gel using 20% ethyl acetate in hexanes to give the desired product.

2- (4-chloro-5-nitro-3-methyl-2-pyridinyl) cyclopropaneethanol

Ethyl 2- (4-chloro-5-nitro-3-methyl-2-pyridinyl) cyclopropaneacetate (0.82 g, 2.7 mmol) is dissolved in dry THF (6 mL). Lithium aluminum hydride (52.2 mg, 1.4 mmol) is added to the solution and the mixture is stirred at room temperature for 1 hour. The reaction mixture is quenched with saturated aqueous sodium potassium stannate solution (15 mL) and the aqueous solution is extracted with ether. The combined organic layers are dried over MgSO 4 and concentrated to afford the desired product as an oil.

2- (4-chloro-5-nitro-3-methyl-2-pyridinyl) cyclopropaneacetaldehyde

2- (4-Chloro-5-nitro-3-methyl-2-pyridinyl) cyclopropaneethanol (0.66 g, 2.6 mmol) was dissolved in CH ₂ Cl ₂ (3 mL) and CH ₂ Cl at −78 ° C. _{To a} solution of dry DMSO (0.47 mL, 6.6 mmol) and oxalyl chloride (0.29 mL, 3.3 mmol) in ₂ (7 mL). After stirring for 15 minutes, triethylamine (1.88 mL, 13.5 mmol) is added and the mixture is further stirred for 5 minutes at -78 ° C and for 10 minutes at 0 ° C. The reaction is then quenched with water and extracted with CH ₂ Cl ₂ . The combined organic layers are washed with water, dried over MgSO 4 and concentrated to give the desired product.

Diethyl [(4-chloro-5-nitro-3-methyl-2-pyridinyl) cyclopropanemethylmethylene] -malonate

Piperidine (0.65 mL), acetic acid (0.65 mL) and diethyl malonate (2.16 mL, 14.2 mmol) were added 2- (4-chloro-5-nitro-3-methyl-2-pyridine in ethanol (25 mL). To a solution of diyl) cyclopropaneacetaldehyde (0.65 g, 2.5 mmol) and the reaction mixture is heated under reflux for 4 h under argon. The solvent is removed and the residue is dissolved in ether. The ether layer is washed with water and brine, dried over MgSO 4 and concentrated. The desired product is purified by flash chromatography on silica gel using 20% ethyl acetate in hexanes.

Ethyl 8-chloro-1-cyclopropyl-7-nitro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (precursor I)

A solution of diethyl [(4-chloro-5-nitro-3-methyl-2-pyridinyl) cyclopropanemethyl-methylene] malonate (0.33 g, 0.832 mmol) in diphenyl ether (15 mL) at 220 ° C. Heat for 45 minutes and then cool to room temperature. The desired product is purified by flash chromatography on silica gel using a hexane / ethyl acetate gradient.

3-Chloro-4,5-difluoroanthranylic acid

To a solution of 4,5-difluoroanthranilic acid (12.25 g, 71 mmol) in CH ₂ CL ₂ (125 mL) was added acetic acid (50 mL) and hypochlorous acid tert-butyl ester (8.75 mL, 78 mmol). do. After 2 hours, the reaction mixture is diluted with EtOAc and washed with water and brine. The organic layer is dried over MgSO ₄ , filtered and concentrated. The resulting residue is purified by flash chromatography using 5% isopropyl alcohol-1% formic acid-94% CH ₂ Cl ₂ to afford the desired product.

2-Bromo-3-chloro-4,5-difluorobenzoic acid

A solution of cuprous bromide (19.12 g, 85.9 mmol) in acetonitrile (175 mL) was cooled at 0 ° C., followed by tert-butyl nitrite (12.8 mL, 107.3 mmol) and 3-chloro-4,5-di Fluoranthranylic acid (14.75 g, 71 mmol) is added. The mixture is slowly warmed to room temperature and after 20 hours the solvent is removed in vacuo. The resulting residue is dissolved in ethyl acetate and washed with 1.0 M hydrochloric acid, water and brine. The organic layer is dried over MgSO ₄ and filtered. The filtrate is concentrated in vacuo and purified by flash chromatography using 5% isopropyl alcohol-1% formic acid-94% CH ₂ Cl ₂ to afford the desired product.

3-Chloro-cyclopropylamino-4,5-difluorobenzoic acid

Triethylamine in isopropyl alcohol (4.9 mL, 35.19 mmol), cupric acetate monohydrate (0.50 g, 2.5 mmol), potassium acetate (5.77 g, 58.6 mmol), cyclopropyl amine (4.20 mL, 58.7 in a sealed tube mmol), and a mixture of 2-bromo-3-chloro-4,5-difluorobenzoic acid (7.96 g, 29.3 mmol) is stirred at 80 ° C. After 16 h, the reaction mixture is concentrated in vacuo and the resulting residue is dissolved in EtOAc. The organic layer is washed with 1.0 M hydrochloric acid, water and brine. The organic layer is dried over MgSO ₄ and filtered. The filtrate is concentrated in vacuo and purified by flash chromatography using 5% isopropyl alcohol-1% formic acid-94% CH ₂ Cl ₂ to afford the desired product.

(3-Chloro-2-cyclopropylamino-4,5-difluorobenzoyl) -hydrazinecarboxylic acid tert-butyl ester

Tert-butyl carbazate (3.34 g, 25.4 mmol) in a solution of 3-chloro-2-cyclopropylamino-4,5-difluorobenzoic acid (4.18 g, 16.9 mmol) in CH ₂ Cl ₂ (60 mL) ) And 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide (2.43 g, 25.4 mmol). After 16 h, the reaction mixture is diluted with CH ₂ Cl ₂ and washed with saturated NaHCO ₃ , water and brine. The organic layer is dried over MgSO ₄ and filtered. The filtrate is concentrated in vacuo and purified by flash chromatography using 33% EtOAc in hexanes to afford the desired product.

8-chloro-1-cyclopropyl-6,7-difluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl) carbamic acid tert-butyl ester (precursor J)

Potassium carbonate (7.38 g, in a solution of (3-chloro-2-cyclopropylamino-4,5-difluorobenzoyl) hydrazinecarboxylic acid tert-butyl ester (3.86 g, 10.7 mmol) in THF (100 mL) 53.4 mmol) and tripphosgene (4.12 g, 13.9 mmol) are added. The reaction mixture is heated at reflux for 90 minutes, cooled to room temperature and diluted with EtOAc. The organic layer is washed with water and brine, then dried over MgSO ₄ and filtered. The filtrate is concentrated in vacuo and purified by flash chromatography using 33% EtOAc in hexanes to afford the desired product.

4,5-Difluoro-2-nitrobenzoic acid ethyl ester

4,5-Difluoro-2-nitrobenzoic acid (1.93 g, 9.5 mmol) in CH ₂ Cl ₂ (30 mL) was cooled to 0 ^° C. under argon atmosphere, oxalyl chloride (1.0 mL, 11.5 mmol), Then treated with anhydrous DMF (2 drops). The mixture is warmed to room temperature and stirred for 2 hours. The solution is co-evaporated with toluene to produce an oil which is placed in CH ₂ Cl ₂ (30 ml), cooled to 0 ^° C. under argon and treated with anhydrous ethanol (6 mL). After 5 hours at room temperature, the solution is poured into saturated NaHCO ₃ and extracted with chloroform. The organic phase is washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to afford the desired product.

4,5-Difluoro-3- (trimethylstannyl) -2-nitrobenzoic acid ethyl ester

To a solution of (tert-butyldimethylsilyl) -tert-butylamine (2.88 mL, 12 mmol) in THF (15 mL) at -78 ° C. under argon n-butyllithium (7.67 mL, 1.5 M in hexane, 11.5 mmol) is added and the solution is warmed to 0 ° C. to give a solution of LiBSBA. In a separate flask, a solution of 4,5-difluoro-2-nitrobenzoic acid ethyl ester (2.20 g, 9.5 mmol) in THF (35 mL) was cooled to −78 ° C. under argon and Me ₃ SnCl (5.7 mL, 2.5 M in THF, 14.3 mmol) is added. The LiBSBA solution is then added dropwise while keeping the internal temperature below -74 ° C. The resulting mixture is stirred at −78 ° C. for 30 minutes and then partitioned between 1 M HCl and Et ₂ O. The aqueous phase is separated and extracted with ether. The combined organic phases are washed with 1 M HCl (3 times) and brine, dried over MgSO ₄ and concentrated. Purification by flash chromatography on silica gel using 10% acetone in hexanes affords the desired product.

4,5-Difluoro-3-methyl-2-nitrobenzoic acid ethyl ester

Tris (dibenzylideneacetone) dipalladium (3.29 g, 3.6 mmol), tri-o-tolylphosphine (4.38 g, 14.3 mmol), cuprous chloride (0.71 g, 7.1 mmol) and potassium carbonate (0.99 g , 7.1 mmol) is placed under argon. After addition of DMF (250 mL), the mixture was stirred at room temperature for 5 minutes, then 4,5-difluoro-3- (trimethylstannyl) -2-nitrobenzoic acid ethyl ester in DMF (200 mL) A solution of (2.81 g, 7.1 mmol) and methyl iodide (35.6 mL, 0.2 M, 7.1 mmol) in DMF are added sequentially. The resulting mixture is stirred at 50 ° C. for 90 minutes under argon. After cooling to room temperature, the reaction mixture is filtered and concentrated under reduced pressure by azeotropic removal of DMF with toluene. Purify the residue by flash chromatography on silica gel using a mixture of 2: 1, 1: 1 and 2: 3 hexanes and EtOAc as eluent to afford the desired product.

2-Amino-4,5-difluoro-3-methyl-benzoic acid ethyl ester

4,5-Difluoro-3-methyl-2-nitrobenzoic acid ethyl ester (1.26 g, 5.1 mmol) is combined with ethanol (20 mL) and 10% Pd / C catalyst (0.13 g) and the mixture is hydrogen Under shaking (40 psi) for 6 hours at room temperature. The catalyst is removed by filtration through celite and the solvent is evaporated to yield the desired product.

2-cyclopropylamino-4,5-difluoro-3-methylbenzoic acid ethyl ester

To a solution of 2-amino-4,5-difluoro-3-methyl-benzoic acid ethyl ester (1.1 g, 5.1 mmol) in anhydrous ethanol, molecular sieve (3x), acetic acid (3 mL) and [(1- Add methoxycyclopropyl) oxy] trimethylsilane (4.1 mL, 20.4 mmol). After 30 minutes, sodium cyanoborohydride (1.63 g, 25.9 mmol) is added and the reaction mixture is heated under reflux. After 16 hours, the reaction mixture is cooled to room temperature and filtered, the filter cake is washed with ethanol and the combined filtrates are concentrated in vacuo to give a viscous oil. This oil is dissolved in ethyl acetate and the solution is washed with 1 M HCl, water and brine. The organic layer is dried over MgSO ₄ , filtered and the filtrate is concentrated in vacuo to afford the desired product as a beige solid.

1-cyclopropyl-6,7-difluoro-8-methyl-1H-quinazolin-2,4-dione

Chlorosulfonylisocyanate (0.69 g, in a solution of 2-cyclopropylamino-4,5-difluoro-3-methylbenzoic acid ethyl ester (1.24 g, 4.9 mmol) in dry CH ₂ Cl ₂ (25 mL) under argon, 4.9 mmol) is added. This solution is left at room temperature for 4 hours and then the solvent is removed under reduced pressure. The residue is cooled at −20 ° C. and cold saline solution (25 mL) buffered with NaHCO ₃ is added. This solution is allowed to warm to room temperature for 1 hour. The volume is reduced by half with a stream of nitrogen and the solids are collected by filtration. The dry solid is added to a solution of triethylamine (1.13 mL, 8.1 mmol) in THF (50 mL) and the mixture is heated at reflux overnight. The reaction mixture is cooled, the solvent is removed under reduced pressure, and the residue is dissolved in water (22.5 mL) and then acidified to pH 1-2 with 1 M HCl. The resulting precipitate is collected by filtration.

3-amino-1-cyclopropyl-6,7-difluoro-8-methyl-1H-quinazolin-2,4-dione (precursor K)

To a solution of 1-cyclopropyl-6,7-difluoro-8-methyl-1H-quinazolin-2,4-dione (0.467 g, 1.85 mmol) in DMF (1.5 mL) and dioxane (1.5 mL). NaH (60% dispersion in oil, 89 mg, 2.2 mmol) is added. This solution is heated at 60 ° C. for 10 minutes and cooled to room temperature. O- (2,4-dinitrophenyl) hydroxylamine (0.368 g, 1.85 mmol) is added to this cooling solution and the solution is heated at 80 ° C. for 30 minutes. The resulting red solution is cooled to room temperature, poured over crushed ice and the mixture is extracted with EtOAc. The combined organic layers are dried over MgSO ₄ , filtered and the solvent is removed under reduced pressure. The resulting solid is triturated with Et ₂ O and air dried to afford the desired product.

b. Preparation of Precursor-7-position portion:

3 (R)-(tert-butoxycarbonyl) 2,2-dimethyl-4-oxazolidinecarboxaldehyde

A solution of methyl 3 (R)-(tert-butoxycarbonyl) -2,2-dimethyl-4-oxazolidinecarboxylate (6.5 g, 25.0 mmol) was dissolved in toluene (40 mL) and -78 Cool to ° C. To the above is added dropwise a solution of diisobutylaluminum hydride ("DIBAL") (33.2 mL, 1 M, 33.2 mmol) to maintain the internal temperature below -60 ° C. After addition, the resulting solution is stirred at −78 ° C. for 30 minutes, then slowly warmed to 0 ° C. for 2 hours. This mixture is quenched by the addition of water. The organic layer is separated and the aqueous layer is extracted once with ethyl acetate. The combined extracts are dried over anhydrous MgSO ₄ and evaporated. The residue is purified by flash chromatography using ethyl acetate-hexanes.

3 (R)-(tert-butoxycarbonyl) 2,2-dimethyl-4- (1-hydroxy-propyl) -oxazolidine

EtMgBr (5.04 g, 22.0 mmol) in a solution of 3 (R)-(tert-butoxycarbonyl) 2,2-dimethyl-4-oxazolidinecarboxaldehyde (5.04 g, 22.0 mmol) in THF (26 mL) at −78 ° C. A solution of 26.4 mL, 1 M in THF) is added dropwise. After addition, the resulting solution is warmed to 0 ° C. for 1.5 h and water is added to quench the reaction. The mixture is partitioned between brine and EtOAc and the aqueous layer is extracted twice more with EtOAc. The combined extracts are dried over MgSO ₄ and evaporated under reduced pressure. The crude product is purified by flash chromatography using EtOAc-hexanes to give the desired product.

3 (R)-(tert-butoxycarbonyl) 2,2-dimethyl-4- (1-oxo-propyl) -oxazolidine

A solution of oxalyl chloride (2.08 mL, 23.8 mmol) in CH ₂ Cl ₂ (70 mL) is cooled in a dry ice / acetone bath and dimethyl sulfoxide (3.53 mL, 49.7 mmol) is added dropwise above. After stirring for 5 minutes at this temperature, 3 (R)-(tert-butoxycarbonyl) 2,2-dimethyl-4- (1-hydroxy-propyl) -oxazolidine in CH ₂ Cl ₂ ( 5.15 g 19.9 mmol) is added at a rate such that the internal temperature is maintained below -65 ° C. The resulting mixture is stirred at −78 ° C. for 30 minutes and triethylamine (13.8 mL, 99 mmol) is added in portions. Continue stirring for an additional 5 minutes. The cooling bath is removed and the reaction temperature is raised to room temperature over 30 minutes. Water is added to quench the reaction. The organic layer is separated and the aqueous layer is extracted with CH ₂ Cl ₂ (twice). The combined extracts are washed with brine, dried over MgSO ₄ and evaporated under reduced pressure. The residue is purified by flash chromatography on silica using EtOAc-hexanes.

3 (S)-(tert-butoxycarbonyl) 2,2-dimethyl-4- (1-buten-2yl) -oxazolidine

To a suspension of (CH ₃ ) PPh ₃ Br (8.59 g, 24 mmol) in anhydrous THF (40 mL) add t-BuOK (2.7 g, 24 mmol) in portions at room temperature. After stirring for 10 minutes, the yellow mixture was poured into 3 (R)-(tert-butoxycarbonyl) 2,2-dimethyl-4- (1-oxo-propyl) -oxazolidine (4.12 g, 16.0 in THF). mmol) solution. The mixture is stirred for an additional 10 minutes and then partitioned between brine and EtOAc. The organic layer is separated and the aqueous layer is extracted with EtOAc (twice). The combined extracts are dried over MgSO ₄ and evaporated under reduced pressure. The residue is treated with ether and the white solid formed is filtered off. The filtrate is evaporated and the residue is purified by flash chromatography on silica gel using EtOAc-hexanes.

2 (S) -tert-butoxycarbonylamino-3-methylene-pentanol

P-TsOHH ₂ O (0.484 g, 2.5 mmol) and 3 (S)-(tert-butoxycarbonyl) 2,2-dimethyl-4- (1-buten-2yl)-in MeOH (100 mL) A solution of oxazolidine (3.25 g, 12.7 mmol) is heated at 50-60 ° C. for 18 hours. After cooling, the solvent is evaporated to 1/3 of its volume and diluted with EtOAc. This mixture is washed with saturated NaHCO ₃ solution. The organic layer is separated and the aqueous layer is extracted with EtOAc (twice). The combined extracts are dried over anhydrous MgSO ₄ and evaporated. The residue is purified by flash chromatography on silica gel using EtOAc-hexanes.

2 (S) -tert-butoxycarbonylamino-3-methylene-1- (4-toluenesulfonylyloxy) -pentane

Triethylamine (1.07 mL, 7.7 mmol), p-toluenesulfonyl chloride (1.46 g, 7.7 mmol) in CH ₂ Cl ₂ (20 mL) and 2 (S) -tert-butoxycarbonylamino-3-methylene- A solution of pentanol (1.38 g. 6.4 mmol) is heated under reflux for 3 hours. After cooling, the solution is washed with saturated sodium bicarbonate solution, 1% aqueous HCl and water, and the organic phase is dried over anhydrous MgSO ₄ and evaporated. The residue is purified by flash chromatography on silica gel using EtOAc-hexanes.

2 (S) -tert-butoxycarbonylamino-3-methylene-N- (2-methyl-2-propenyl) -pentylamine

A solution of 2-tert-butoxycarbonylamino-3-methylene-1- (4-toluenesulfonylyloxy) -pentane (1.95 g, 5.3 mmol) and metalylamine (2.34 mL, 26.4 mmol) was prepared at 45 ° C. Heated for 4 hours. Excess reagent was distilled off under vacuum. The residue was purified by flash chromatography on silica gel using CH ₂ Cl ₂ -MeOH.

2 (S) -tert-butoxycarbonylamino-3-methylene-N- (2-methyl-2-propenyl) -N-trifluoroacetyl-pentylamine

2 (S) -tert-butoxycarbonylamino-3-methylene-N- (2-methyl-2-propenyl) -pentylamine (1.27 g, 4.7 mmol), trifluoroacetic anhydride (0.74 mL, 5.2 mmol) and Et ₃ N (0.79 mL, 5.7 mmol) are stirred for 30 minutes under argon at a temperature below 10 ° C. The mixture is washed with saturated NaHCO ₃ , dried over anhydrous MgSO ₄ and evaporated. The residue is purified by flash chromatography on silica gel using EtOAc-hexanes.

1,2,3,6-tetrahydro-3 (S) -tert-butoxycarbonylamino-4-ethyl-5-methyl-1-trifluoroacetyl-pyridine

2 (S) -tert-butoxycarbonylamino-3-methylene-N- (2-methyl-2-propenyl) -N-trifluoroacetyl-pentylamine (1.46 g, 4.0 mmol) and groove catalyst ( Grubb s catalyst) (benzylidene-bis (tricyclohexylphosphine) dichlororuthenium, 0.329 g, 0.4 mmol) is dissolved in CH ₂ Cl ₂ (150 mL) and the solution is heated under reflux under argon for 20 hours. do. The solvent is evaporated and the residue is purified by flash chromatography on silica gel using EtOAc-hexanes.

3 (S) -tert-butoxycarbonylamino-4 (R) -ethyl-5 (S) -methyl-1-trifluoroacetyl-piperidine

PtO ₂ (0.062 g) and 1,2,3,6-tetrahydro-3-tert-butoxycarbonylamino-4-ethyl-5-methyl-1-trifluoroacetyl-pyridine in EtOH (60 mL) (1.08 g, 3.2 mmol) is treated with H ₂ (1 atm) for 48 hours. The catalyst is removed by filtration and the filtrate is evaporated. The crude product is purified by flash chromatography using 10-20% EtOAc-hexanes.

3 (S) -tert-butoxycarbonylamino-4 (R) -ethyl-5 (S) -methyl-piperidine (precursor L)

K ₂ CO ₃ (1.8 g, 13 mmol) and 3 (S) -tert-butoxycarbonylamino-4 (R) -ethyl-5 (S) in H ₂ O (10 mL) and MeOH (40 mL) A mixture of -methyl-1-trifluoroacetyl-piperidine (1.05 g, 3.1 mmol) is heated under reflux for 30 minutes. The solid is removed by filtration and the filtrate is concentrated. The residue is partitioned between H ₂ O and CH ₂ Cl ₂ . The organic layer is separated and the aqueous layer is extracted with CH ₂ Cl ₂ . The combined extracts are dried over anhydrous MgSO ₄ and evaporated.

2 (S) -Amino-pentanedioic acid dimethyl ester hydrochloride

Suspension of L-glutamic acid (18.0 g, 122 mmol) in methanol (120 mL) is cooled in an ice bath. The mixture is treated dropwise with thionyl chloride (12.45 mL, 171 mmol) and the mixture is stirred at rt for 18 h. The reaction is concentrated, toluene is added to the residue and the volatiles are removed by evaporation. This process is repeated two more times to obtain the desired product.

2 (S) -tert-butoxycarbonylamino-pentanedioic acid dimethyl ester

A solution of 2 (S) -amino-pentanedioic acid dimethyl ester hydrochloride (24.3 g, 115 mmol) in methanol (150 mL) is treated with triethylamine (31.5 mL, 226 mmol). Solid di-tert-butyl dicarbonate (33 g, 151 mmol) is added. After 18 hours, the solvent is removed and the residue is dissolved in CH ₂ Cl ₂ . The solution is washed twice with 1N HCl, once with brine and dried over Na ₂ SO ₄ . The absorbent used is removed and the solvent is evaporated to yield the desired product.

2 (S) -tert-butoxycarbonylamino-4 (S) -methyl-pentanedioic acid dimethyl ester

A solution of lithium hexamethyldisilylazide (152.6 mL, 1M in THF, 152.6 mmol) is cooled in a dry ice / acetone bath under argon. A solution of 2 (S) -tert-butoxycarbonylamino-pentanedioic acid dimethyl ester (20 g, 72.6 mol) in THF (200 mL) was added via cannula while maintaining the temperature below -60 ° C. do. After 30 minutes at −78 ° C. methyl iodide (9 mL, 145 mmol) is added via cannula as quickly as possible. The reaction mixture is stirred at −78 ° C. for 4.5 h and then quenched with 1 N HCl (190 mL). The aqueous layer is extracted with EtOAc (350 mL, 3 times). The combined extracts are washed with saturated NaHCO ₃ and brine, dried over Na ₂ SO ₄ and concentrated to give a yellow oil which is purified by flash chromatography using 20% EtOAc / hexanes.

(4-Hydroxy-1 (S) -hydroxymethyl-3 (S) -methyl-butyl) -carbamic acid tert-butyl ester

A solution of 2 (S) -tert-butoxycarbonylamino-4 (S) -methyl-pentanedioic acid dimethyl ester (10.85 g, 37.5 mmol) in 1: 1 EtOH / THF (250 mL) was dissolved in CaCl ₂ (16.65 g, 150 mmol) and the resulting slurry is cooled in an ice bath under argon. To the mixture is added NaBH ₄ (11.35 g, 300 mmol) in portions. After 1 hour the ice bath is removed and the reaction mixture is stirred for 16 hours at room temperature. The mixture is quenched with 10% Na ₂ CO ₃ and water and the resulting dark white slurry is extracted with EtOAc (3 times). The combined organic layers are washed with brine, dried over Na ₂ S0 ₄ and concentrated to afford the desired product.

Methanesulfonic acid 2 (S) -tert-butoxycarbonylamino-5-methanesulfonyloxy-4 (S) -methyl-pentyl ester

A solution of (4-hydroxy-1 (S) -hydroxymethyl-3 (S) -methyl-butyl) -carbamic acid tert-butyl ester (8.75 g 37.5 mmol) in CH ₂ Cl ₂ (130 mL) Cool in an ice bath under and add triethylamine (20.9 mL, 150 mmol) through a syringe. Methanesulfonyl chloride (8.7 mL, 112 mmol) is added dropwise and the mixture is stirred at 0 ° C. for 1 hour. The reaction is diluted with CH ₂ Cl ₂ , washed with saturated NaHCO ₃ and brine, dried over Na ₂ SO ₄ and concentrated to the desired product.

(1-Benzyl-5 (S) -methyl-piperidin-3 (S) -yl) -carbamic acid tert-butyl ester

Of methanesulfonic acid 2 (S) -tert-butoxycarbonylamino-5-methanesulfonyloxy-4 (S) -methyl-pentyl ester (14.6 g, 37.5 mmol) in benzylamine (81.9 mL, 750 mmol) The solution is heated at 70 ° C. for 24 hours. The mixture is then cooled to room temperature and poured into 1 N NaOH (500 ml). The resulting oily aqueous mixture is extracted with hexane (300 ml, 3 times). The combined hexane extracts are dried over MgSO 4 and the volatiles are removed in vacuo to give an oil which is purified by flash chromatography using 1-10% gradient EtOAc / hexanes.

(5 (S) -Methyl-piperidin-3 (S) -yl) -carbamic acid tert-butyl ester (precursor M)

10% Pd / in a solution of (1-benzyl-5 (S) -methyl-piperidin-3 (S) -yl) -carbamic acid tert-butyl ester (9.8 g, 32.2 mmol) in EtOH (300 mL) C (1 g) is added. This mixture is treated with hydrogen (30 psi) for 16 hours on a Parr apparatus. The reaction mixture is filtered through celite, the filtrate is concentrated and the residue is purified by flash chromatography on silica gel using 10% MeOH / CHCl ₃ with 1% NH ₄ OH to afford the desired product. .

2 (S) -Amino-pentanedioic acid dimethyl ester hydrochloride

Suspension of L-glutamic acid (6.00 g, 40.7 mmol) in methanol (40 mL) is cooled in an ice bath. The mixture is treated dropwise with thionyl chloride (4.15 mL, 56.9 mmol) and the reaction mixture is stirred at rt for 18 h. The volatiles are then removed by evaporation under vacuum, toluene is added to the residue and evaporated. This process is repeated twice to give the desired product.

2 (S) -tert-butoxycarbonylamino-pentanedioic acid dimethyl ester

A solution of 2 (S) -amino-pentanedioic acid dimethyl ester hydrochloride (8.12 g, 38.4 mmol) in methanol (50 mL) was purified by triethylamine (10.5 mL, 75.3 mmol) and solid di-tert-butyl dicarbo. Treated with Nate (10.91 g, 50.0 mmol). After 18 hours, the solvent is removed and the residue is dissolved in CH ₂ Cl ₂ and the solution is washed with 1N HCl (10 mL, twice) and brine (5 mL, once). The solution is dried over Na ₂ SO ₄ and the absorbent used is filtered off and then the solvent is evaporated to leave the desired product.

2 (S) -tert-butoxycarbonylamino-4 (S) -ethyl-pentanedioic acid dimethyl ester

A solution of lithium bis (trimethylsilyl) amide (10.5 mL, 1M in THF, 10.5 mmol) is cooled in a dry ice / acetone bath. A solution of 2 (S) -tert-butoxycarbonylamino-pentanedioic acid dimethyl ester (1.38 g, 5.0 mmol) in THF (15 mL) is added dropwise while maintaining the temperature below -70 ° C. After 30 minutes, ethyl iodide (1.2 mL, 15.0 mmol) is added dropwise. The reaction mixture is stirred for 1 hour and then quenched with 1 N HCl (10 mL). The aqueous layer is extracted with EtOAc (5 mL, 3 times) and the combined extracts are washed with brine and dried over Na ₂ S0 ₄ . The absorbent used is removed by filtration and the volatiles are evaporated under reduced pressure to leave an oil which is purified by chromatography using 15-25% EtOAc / hexanes.

(4-Hydroxy-1 (S) -hydroxymethyl-3 (S) -ethyl-butyl) -carbamic acid tert-butyl ester

A solution of 2 (S) -tert-butoxycarbonylamino-4 (S) -ethyl-pentanedioic acid dimethyl ester (0.69 g, 2.3 mmol) in 1: 1 EtOH / THF (16 mL) was dissolved in CaCl _2. (1.01 g, 9.1 mmol) and cooled in an ice bath. To the mixture is added NaBH ₄ (0.69 g, 18.2 mmol) all at once. After 1 hour, the ice bath is removed and the reaction is stirred for 16 hours at room temperature. The reaction mixture is quenched with saturated Na ₂ CO ₃ and water and the aqueous layer is extracted with EtOAc (3 times). The combined extracts are washed with brine and dried over Na ₂ SO ₄ to afford the desired product upon removal of the solvent.

Methanesulfonic acid 2 (S) -tert-butoxycarbonylamino-5-methanesulfonyloxy-4 (S) -methyl-pentyl ester

A solution of (4-hydroxy-1 (S) -hydroxymethyl-3 (S) -ethyl-butyl) -carbamic acid tert-butyl ester (0.53 g, 2.1 mmol) in CH ₂ Cl ₂ (8 mL) Treat with triethylamine (1.1 mL, 7.9 mmol) and cool in an ice bath. Methanesulfonyl chloride (0.48 mL, 6.2 mmol) is added dropwise. After 1 h, the reaction mixture is diluted with CH ₂ Cl ₂ and the organic layer is washed with saturated NaHCO ₃ and brine and dried over Na ₂ SO ₄ . The absorbent used is removed by filtration and the solvent is removed by evaporation under reduced pressure to afford the desired product.

 (1-Benzyl-5 (S) -ethyl-piperidin-3 (S) -yl) -carbamic acid tert-butyl ester

Solution of methanesulfonic acid 2 (S) -tert-butoxycarbonylamino-5-methanesulfonyloxy-4 (S) -methyl-pentyl ester (0.72 g, 1.8 mmol) in CH ₂ Cl ₂ (8 mL) Is treated with benzylamine (1.1 mL, 10.0 mmol) and the mixture is heated at reflux for 24 h. The reaction mixture is then cooled to room temperature and diluted with chloroform. The organic solution is washed with 5% citric acid and brine and dried over Na ₂ SO ₄ . The absorbent used is removed by filtration and the solvent is removed by evaporation under reduced pressure to afford the desired product.

(5 (S) -Ethyl-piperidin-3 (S) -yl) -carbamic acid tert-butyl ester (precursor N)

To a solution of (1-benzyl-5 (S) -ethyl-piperidin-3 (S) -yl) -carbamic acid tert-butyl ester (0.125 g, 0.393 mmol) in EtOH (4 mL) 10% Pd ( OH) _{2 / C (} 0.075 g) is added. The mixture is placed under hydrogen atmosphere (balloon) and stirred for 18 hours. The reaction mixture is filtered through celite and the filtrate is concentrated to give the desired product.

4 (S) -tert-butoxycarbonylamino-2,2-dimethyl-pentanedioic acid dimethyl ester

To a stirred solution of potassium bis (trimethylsilylamide) (44.4 mL, 0.5 M in toluene, 22.2 mmol) in dry THF (22 mL) at −78 ° C. 2 (S) -tert-part in dry THF (26 mL) A solution of oxycarbonylamino-4 (S) -methyl-pentanedioic acid dimethyl ester (2.14 g, 7.4 mmol) is added over 5 minutes under argon atmosphere. The resulting pale yellow solution is stirred at −78 ° C. for 1 h, followed by the addition of methyl iodide (1.38 mL, 22.2 mmol). Stirring is continued at −78 ° C. for 0.5 h, then the white slurry is poured into saturated NH ₄ Cl solution (200 mL) and the resulting mixture is extracted with Et ₂ O (150 mL, 3 times). The ether extracts are combined, dried over Na ₂ SO ₄ , concentrated in vacuo and purified by flash chromatography using 15% EtOAc / hexanes to afford the desired product.

(4-Hydroxy-1 (S) -hydroxymethyl-3,3-dimethyl-butyl) -carbamic acid tert-butyl ester

A solution of 4 (S) -tert-butoxycarbonylamino-2,2-dimethyl-pentanedioic acid dimethyl ester (1.97 g, 6.5 mmol) in 1: 1 EtOH / THF (45 mL) was dissolved in CaCl _2. (2.89 g, 26.0 mmol) and the resulting slurry is cooled in an ice bath under argon. To the mixture is added NaBH ₄ (1.97 g, 52.1 mmol) in portions. After 1 hour, the ice bath is removed and the reaction mixture is stirred for 16 hours at room temperature. The mixture is quenched with 10% Na ₂ CO ₃ and water and the resulting dark white slurry is extracted with EtOAc (3 times). The combined organic layers are washed with brine, dried over Na ₂ S0 ₄ and concentrated to afford the desired product.

Methanesulfonic acid 2 (S) -tert-butoxycarbonylamino-5-methanesulfonyloxy-4,4-dimethyl-pentyl ester

A solution of (4-hydroxy-1 (S) -hydroxymethyl-3-dimethyl-butyl) -carbamic acid tert-butyl ester (1.56 g, 6.3 mmol) in CH ₂ Cl ₂ (25 mL) under argon Cool in an ice bath and add triethylamine (3.5 mL, 25.1 mmol) via syringe. Methanesulfonyl chloride (1.5 mL, 19.4 mmol) is added dropwise and the mixture is stirred at 0 ° C. for 1 hour. The reaction mixture is diluted with CH ₂ Cl ₂ , washed with saturated NaHCO ₃ and brine, dried over Na ₂ SO ₄ and concentrated to afford the desired product.

(1-benzyl-5,5-dimethyl-piperidin-3 (S) -yl) -carbamic acid tert-butyl ester

Solution of methanesulfonic acid 2 (S) -tert-butoxycarbonylamino-5-methanesulfonyloxy-4-dimethyl-pentyl ester (2.55 g, 6.3 mmol) in benzylamine (15 mL, 137 mmol) Heated at 70 ^° C. for 24 h. The mixture is then cooled to room temperature and poured into 1 N NaOH (45 ml). The resulting oily aqueous mixture is extracted with hexane (25 ml, 3 times). The combined hexane extracts are dried over MgSO ₄ and the volatiles are removed in vacuo to give an oil which is purified by flash chromatography using 1-10% gradient EtOAc / hexanes.

(5,5-Dimethyl-piperidin-3 (S) -yl) -carbamic acid tert-butyl ester (precursor O)

To a solution of (1-benzyl-5-dimethyl-piperidin-3 (S) -yl) -carbamic acid tert-butyl ester (0.66 g, 2.1 mmol) in EtOH (20 mL) 10% Pd / C ( 0.19 g) is added. This mixture is treated with hydrogen (30 psi) for 16 hours on a Parr apparatus. The reaction mixture is filtered through celite, the filtrate is concentrated and the residue is purified by flash chromatography on silica gel using 10% MeOH / CHCl ₃ with 1% NH ₄ OH to afford the desired product. .

1- (2-tert-butoxycarbonylamino-2-methoxycarbonyl-ethyl) -cyclobutanecarboxylic acid methyl ester

Sodium hydride (60% in mineral oil, 0.48 g, 12.0 mol) at room temperature under argon was converted to 2 (S) -tert-butoxycarbonylamino-pentanedioic acid dimethyl ester (1.10 g, 4.0 in anhydrous DMF (20 mL). mmol), and after 0.5 h 1,3-dibromopropane (1.21 g, 6.0 mmol) is added to the mixture. The reaction mixture is stirred at 30-35 ° C. for 4 hours and then left overnight at room temperature. This mixture is poured into a mixture of ice water (60 mL) and EtOAc (60 mL) and then acidified to pH 2 by the slow addition of 6 N HCl. The layers are separated and the organic layer is washed successively with water and brine, dried over Na ₂ SO ₄ and concentrated. The residue is purified by flash chromatography on silica gel using 20% EtOAc / hexanes to give the desired product.

[1-hydroxymethyl-2- (1-hydroxymethyl-cyclobutyl) -ethyl] -carbamic acid tert-butyl ester

Of 1- (2-tert-butoxycarbonylamino-2-methoxycarbonyl-ethyl) -cyclobutanecarboxylic acid methyl ester (0.82 g, 2.6 mmol) in 1: 1 EtOH / THF (18 mL) The solution is treated with CaCl ₂ (1.16 g, 10.5 mmol) and the resulting slurry is cooled in an ice bath under argon. To the mixture is added NaBH ₄ (0.79 g, 20.9 mmol) in portions. After 1 hour, the ice bath is removed and the reaction mixture is stirred for 16 hours at room temperature. The mixture is quenched with 10% Na ₂ CO ₃ and water and the resulting dark white slurry is extracted with EtOAc (3 times). The combined organic layers are washed with brine, dried over Na ₂ S0 ₄ and concentrated to afford the desired product.

Methanesulfonic acid 1- (2-tert-butoxycarbonylamino-3-methanesulfonyloxy-propyl) -cyclobutylmethyl ester

A solution of [1-hydroxymethyl-2- (1-hydroxymethyl-cyclobutyl) -ethyl] -carbamic acid tert-butyl ester (0.64 g, 2.5 mmol) in CH ₂ Cl ₂ (10 mL) under argon Cool in an ice bath and add triethylamine (1.4 mL, 10.0 mmol) through syringe. Methanesulfonyl chloride (0.6 mL, 7.8 mmol) is added dropwise and the mixture is stirred at 0 ° C. for 1 hour. The reaction is diluted with CH ₂ Cl ₂ , washed with saturated NaHCO ₃ and brine, dried over Na ₂ SO ₄ and concentrated to afford the desired product.

(6-benzyl-6-aza-spiro [3.5] non-8-yl) -carbamic acid tert-butyl ester

A solution of methanesulfonic acid 1- (2-tert-butoxycarbonylamino-3-methanesulfonyloxy-propyl) -cyclobutylmethyl ester (0.94 g, 2.3 mmol) in benzylamine (8 mL, 73.2 mmol) Heat at 70 ° C. for 24 hours. The mixture is then cooled to room temperature and poured into 1 N NaOH (20 ml). The resulting oily aqueous mixture is extracted with hexane (10 ml, 3 times). The combined hexane extracts are dried over MgSO ₄ and the volatiles are removed in vacuo to give an oil which is purified by flash chromatography using 1-10% gradient EtOAc / hexanes.

(6-Aza-spiro [3.5] non-8-yl) -carbamic acid tert-butyl ester (precursor P)

Add 10% Pd / C (0.05 g) to a solution of (6-benzyl-6-aza-spiro [3.5] non-8-yl) -carbamic acid tert-butyl ester (0.13 g) in EtOH (5 mL) do. This mixture is treated with hydrogen (30 psi) for 8 hours on a Parr apparatus. The reaction mixture is filtered through celite, the filtrate is concentrated and the residue is purified by flash chromatography on silica gel using 10% MeOH / CHCl ₃ with 1% NH ₄ OH to afford the desired product. .

3 (R)-(tert-butoxycarbonyl) 2,2-dimethyl-4-oxazolidine carboxaldehyde

A solution of methyl 3- (tert-butoxycarbonyl) 2,2-dimethyl-4-oxazolidinecarboxylate (15.00 g, 57.8 mmol) is dissolved in toluene (100 mL) and cooled to -78 ° C. . A solution of diisobutylaluminum hydride (1.0 M, 98.3 mL, 98.3 mmol) is added dropwise to maintain the internal temperature below -60 ° C. After addition, the resulting solution is stirred at −78 ° C. for 30 minutes and then slowly warmed to 0 ° C. within 2 hours. This mixture is quenched by the addition of water. The organic layer is separated and the aqueous layer is extracted once with ethyl acetate. The combined extracts are dried over anhydrous MgSO ₄ and evaporated. The residue is purified by flash chromatography using ethyl acetate-hexanes.

3 (S)-(tert-butoxycarbonyl) -2,2-dimethyl-4-vinyl-oxazolidine

To a suspension of Ph ₃ PCH ₃ Br (24.60 g, 68.8 mmol) in dry THF (40 mL) at room temperature add t-BuOK (7.72 g, 68.8 mmol) in portions. After stirring for 10 minutes, the yellow mixture was poured into a solution of 3 (R)-(tert-butoxycarbonyl) 2,2-dimethyl-4-oxazolidine carboxaldehyde (10.50 g, 45.8 mmol) in THF. Process. The mixture is stirred for an additional 10 minutes and then partitioned between brine and EtOAc. The organic layer is separated and the aqueous layer is extracted with EtOAc (twice). The combined extracts are dried over MgSO ₄ and evaporated under reduced pressure. The residue is treated with ether and the white solid formed is filtered off. The filtrate is evaporated and the residue is purified by flash chromatography on silica gel using EtOAc-hexanes.

2 (S) -tert-butoxycarbonylamino-3-buten-1-ol

P-TsOH, H ₂ O (0.88 g, 4.6 mmol) and 3 (S)-(tert-butoxycarbonyl) -2,2-dimethyl-4vinyl-oxazolidine (10.50) in MeOH (100 mL) g, 46.3 mmol) is heated under reflux for 2 days. After cooling, the solvent is evaporated and the residue is purified by flash chromatography on silica gel using EtOAc-hexanes.

2 (S) -tert-butoxycarbonylamino-3-butenyl-1- (4-toluenesulfonate)

Et ₃ N (6.2 mL, 44.5 mmol), p-toluenesulfonyl chloride (8.42 g, 44.1 mmol) and 2 (S) -tert-butoxycarbonylamino-3-butene in CH ₂ Cl ₂ (120 mL) A solution of -1-ol (6.88 g, 36.8 mmol) is heated under reflux for 3 hours. After cooling, the solution is washed with saturated NaHCO ₃ , dried over anhydrous MgSO ₄ and evaporated. The residue is purified by flash chromatography on silica gel using EtOAc-hexanes.

2 (S) -tert-butoxycarbonylamino-N- (1-prop-2-ynyl) -but-3-enylamine

A solution of 2 (S) -tert-butoxycarbonylamino-3-butenyl-1-toluenesulfonate (10.34 g, 30.3 mmol) and 2-propynylamine (10.4 mL, 151.6 mmol) was added at 45 ° C. Heat for hours. Excess reagent is distilled off under vacuum. The residue is purified by flash chromatography on silica gel using CH ₂ Cl ₂ -MeOH.

2 (S) -tert-butoxycarbonylamino-N- (1-prop-2ynyl) -N-benzyl-but-3-enylamine

Benzyl bromide (0.83 mL, 7.0 mmol) was added to 2 (S) -tert-butoxycarbonylamino-N- (1-prop-2-ynyl) -but-3 in anhydrous Et ₂ O (8 mL) at room temperature. -Dropwise to a stirred solution of enylamine (3.12 g, 13.9 mmol). The mixture is heated under reflux for 1 h and then cooled to 0 ^o C. The white crystals are filtered off and extracted with anhydrous Et ₂ O (50 mL). The filtrate is concentrated in vacuo to yield a cloudy oil. The crude product is purified by flash chromatography on silica gel using 0-5% ether in hexanes to give the desired product. Excess 2 (S) -tert-butoxycarbonylamino-N- (1-prop-2-ynyl) -but-3-enylamine by basifying an aqueous solution of the filtered salt with NaOH (2 M) Recover, then extract with Et ₂ O and concentrate.

3 (S) -tert-butoxycarbonylamino-4 (R) -methyl-5-methylene-1-benzyl-piperidine

N-butyllithium (5.5 mL, 2.5 M in hexanes, 13.8 mmol) was slowly added to a solution of Cp ₂ ZrCl ₂ (2.03 g, 6.9 mmol) in THF (25 mL) at -78 ° C under argon. After stirring at −78 ° C. for 1 hour, 2 (S) -tert-butoxycarbonylamino-N- (1-prop-2ynyl) -N-benzyl-but-3- in THF (5 mL) Enylamine (1.97 g, 6.3 mmol) is added. The yellow solution is warmed over 2 hours and stirred for an additional 2 hours. Methanol (1.6 mL) is added to the resulting dark brown solution, the color of which immediately turns yellow. The mixture is diluted with saturated NaHCO ₃ solution (20 mL) and Et ₂ O (40 mL), the layers are separated and the aqueous layer is extracted with Et ₂ O (100 mL, 3 times). The combined organic extracts are dried (K ₂ CO ₃ ) and concentrated in vacuo to yield a cloudy yellow oil. HPLC analysis showed that the two diastereomers were present in a ratio of about 80:20. The crude product is purified by flash chromatography on silica gel using 3% triethylamine in hexanes to give the main diastereomer as the desired product.

(5-Benzyl-8 (R) -methyl-5-azaspiro [2.5] oct-7-yl) -carbamic acid tert-butyl ester

Zinc dust (7.46 g), cuprous chloride (1.5 g) and Et ₂ O (25 mL) are refluxed for 1 hour. 3 (S) -tert-butoxycarbonylamino-4 (R) -methyl-5-methylene-1-benzyl-piperidine (1.39 g, 4.4 mmol) and diiodomethane (5 mL, 62 mmol) Add. The mixture is heated under reflux for 10 hours, additional diiodomethane (5 mL, 62 mmol) is added and the mixture is heated further under reflux for 15 hours. The reaction mixture is quenched with water, the ether layer is separated and washed with 10% HCl, water and NaHCO ₃ and dried over K ₂ CO ₃ . The absorbent used is removed and concentrated to give an oil which is purified by flash chromatography on silica gel using 10% EtOAc in hexanes.

(8 (R) -Methyl-5-aza-spiro [2.5] oct-7-yl) -carbamic acid tert-butyl ester (precursor Q)

(5-Benzyl-8 (R) -methyl-5-azaspiro [2.5] oct-7-yl) -carbamic acid tert-butyl ester (0.54 g, 1.6 mmol) was added 1,2-dichloroethane (2 mL ) And the mixture is cooled at 0 ° C. A solution of α-chloroethyl chloroformate (0.25 g, 1.8 mmol) in 1,2-dichloroethane (1 mL) is then added dropwise over 15 minutes and stirring is continued at 0 ° C. for 15 minutes. The mixture is heated under reflux for 1 hour, cooled to room temperature and the solvent is removed under reduced pressure. The oily crude residue is dissolved in MeOH (1 mL) and the mixture is heated under reflux for 1 hour. The solvent is again evaporated under reduced pressure, the crude product is dissolved in water (3 mL) and the aqueous layer is extracted with Et ₂ O (1 mL, twice) and with CH ₂ CL ₂ (1 mL, twice). Solid NaHCO ₃ (0.33 g, 3.9 mmol) is added to the aqueous layer (pH = 9.0) and it is extracted with CH ₂ CL ₂ (1 mL, twice). The combined organic layers are dried over Na ₂ S0 ₄ and the volatiles are evaporated to afford the desired product as an oil.

2 (S) -tert-butoxycarbonylamino-N- (2-methyl-2-propenyl) -but-3-enylamine

A solution of 2 (S) -tert-butoxycarbonylamino-3-butenyl-1-toluenesulfonate (5.17 g, 15.1 mmol) and metalylamine (5.4 mL, 75.8 mmol) was stirred at 45 ° C. for 4 hours. Heat. Excess reagent is distilled off under vacuum. The residue is purified by flash chromatography on silica gel using CH ₂ Cl ₂ -MeOH.

2 (S) -tert-butoxycarbonylamino-N- (1-methyl-2-propenyl) -N-benzyl-but-3-enylamine

Benzyl bromide (0.42 mL, 3.5 mmol) was added at room temperature to 2 (S) -tert-butoxycarbonylamino-N- (2-methyl-2-propenyl) -but-3 in anhydrous Et ₂ O (4 mL). -Dropwise to a stirred solution of enylamine (1.68 g, 7.0 mmol). The mixture is heated at reflux for 1 h and then cooled to 0 ° C. The white crystals are filtered off and extracted with anhydrous Et ₂ O (25 mL). The filtrate is concentrated in vacuo to yield a cloudy oil. The crude product is purified by flash chromatography on silica gel using 0-5% ether in hexanes to give the desired product. Excess 2 (S) -tert-butoxycarbonylamino-N- (1-methyl-2-propenyl) -but-3-enylamine was made by basifying an aqueous solution of the filtered salt with NaOH (2 M). Recover and then extract with Et ₂ O and concentrate.

3 (S) -tert-butoxycarbonylamino-4 (R) -methyl-5,5-dimethyl-1-benzyl-piperidine

To a solution of Cp ₂ ZrCl ₂ (1.01 g, 3.5 mmol) in THF (15 mL) at -78 ° C. under argon was slowly added n-butyllithium (2.8 mL, 2.5 M in hexanes, 7.0 mmol). After stirring at −78 ° C. for 1 hour, 2 (S) -tert-butoxycarbonylamino-N- (1-methyl-2-propenyl) -N-benzyl-but-3 in THF (5 mL) -Enylamine (1.06 g, 3.2 mmol) is added. The yellow solution is warmed to room temperature over 2 hours and stirred for an additional 2 hours. Methanol (0.8 mL) is added to the resulting dark brown solution, the color of which immediately turns yellow. The mixture is diluted with saturated NaHCO ₃ solution (10 mL) and Et ₂ O (20 mL), the layers are separated and the aqueous layer is extracted with Et ₂ O (50 mL, 3 times). The combined organic extracts are dried (K ₂ CO ₃ ) and concentrated in vacuo to yield a cloudy yellow oil. The crude product is purified by flash chromatography on silica gel using 3% triethylamine in hexanes to give the main diastereomer as the desired product.

3 (S) -tert-butoxycarbonylamino-4 (R) -methyl-5,5-dimethyl-piperidine (precursor R)

3 (S) -tert-butoxycarbonylamino-4 (R) -methyl-5,5-dimethyl-1-benzyl-piperidine (0.69 g, 2.1 mmol) in methanol (25 mL) 10% Combine with Pd / C (0.07 g) and shake for 15 hours at room temperature under hydrogen atmosphere (40 psi). The catalyst used is removed by filtration through celite and the solvent is removed in vacuo to afford the desired product.

2 (S) -tert-butoxycarbonylamino-N- (2-propenyl) -but-3-enylamine

A solution of 2 (S) -tert-butoxycarbonylamino-3-butenyl-1-toluenesulfonate (3.47 g, 10 mmol) and allylamine (3.8 mL, 50.3 mmol) was heated at 45 ° C. for 4 hours. do. Excess reagent is distilled off under vacuum. The residue is purified by flash chromatography on silica gel using CH ₂ Cl ₂ -MeOH.

2 (S) -tert-butoxycarbonylamino-N- (1-methyl-2-propenyl) -N-benzyl-but-3-enylamine

Benzyl bromide (0.28 mL, 2.3 mmol) was added at room temperature to 2 (S) -tert-butoxycarbonylamino-N- (2-propenyl) -but-3-enylamine in anhydrous Et ₂ O (3 mL). 1.06 g, 4.7 mmol) is added dropwise to the stirred solution. The mixture is heated at reflux for 1 h and then cooled to 0 ° C. The white crystals are filtered off and extracted with anhydrous Et ₂ O (18 mL). The filtrate is concentrated in vacuo to yield a cloudy oil. The crude product is purified by flash chromatography on silica gel using 0-5% ether in hexanes to give the desired product. Excess 2 (S) -tert-butoxycarbonylamino-N- (1-methyl-2-propenyl) -but-3-enylamine was made by basifying an aqueous solution of the filtered salt with NaOH (2 M). Recover and then extract with Et ₂ O and concentrate.

3 (S) -tert-butoxycarbonylamino-4 (R) -methyl-5 (S) -methyl-1-benzyl-piperidine

To a solution of Cp ₂ ZrCl ₂ (0.67 g, 2.3 mmol) in THF (10 mL) at -78 ° C under argon was slowly added -butyllithium (1.85 mL, 2.5 M in hexanes, 4.6 mmol). After stirring at −78 ° C. for 1 hour, 2 (S) -tert-butoxycarbonylamino-N- (2-propenyl) -N-benzyl-but-3-enylamine in THF (3 mL) ( 0.71 g, 2.1 mmol) is added. The yellow solution is warmed to room temperature over 2 hours and stirred for an additional 2 hours. Methanol (0.5 mL) is added to the resulting dark brown solution, the color of which immediately turns yellow. The mixture is diluted with saturated NaHCO ₃ solution (7 mL) and Et ₂ O (15 mL), the layers are separated and the aqueous layer is extracted with Et ₂ O (35 mL, 3 times). The combined organic extracts are dried (K ₂ CO ₃ ) and concentrated in vacuo to yield a cloudy yellow oil. The crude product is purified by flash chromatography on silica gel using 3% triethylamine in hexanes to give the main diastereomer as the desired product.

3 (S) -tert-butoxycarbonylamino-4 (R) -methyl-5 (S) -methyl-piperidine (precursor S)

3 (S) -tert-butoxycarbonylamino-4 (R) -methyl-5 (S) -methyl-1-benzyl-piperidine (0.32 g, 1.0 mmol) in 10% methanol (20 mL) Combine with Pd / C (0.04 g) and shake for 15 hours at room temperature under hydrogen atmosphere (40 psi). The catalyst used is removed by filtration through celite and the solvent is removed in vacuo to afford the desired product.

b. Preparation of the final product

Example 1

7- [3S-amino-5S-methyl-piperidinyl] -1-cyclopropyl-1,4-dihydro-6-fluoro-8-methoxy-4-oxo-3-quinolinecarboxylic acid hydrochloride

1-cyclopropyl-1,4-dihydro-6,7-difluoro-8-methoxy-4-oxo-quinoline-3-carboxylic acid (precursor A) (0.059 g, 0.200 mmol), (5 (S) -Methyl-piperidin-3 (S) -yl) -carbamic acid tert-butyl ester (precursor M) (0.048 g, 0.210 mmol) and triethylamine (0.075 mL) were added N-methyl-pyrroli Dissolve in money (2 mL). The reaction mixture is stirred at 80 ° C. for 5 hours, then poured into an ice / water mixture. The pH is lowered to 2 with dilute HCl and the resulting precipitate is filtered off. The solid is then suspended in ethanol and 6N HCl is added. After 18 hours at room temperature, the desired final product is collected by filtration.

Example 2

7- [3S-amino-5S-ethyl-piperidinyl] -1-cyclopropyl-1,4-dihydro-6-fluoro-8-methoxy-4-oxo-3-quinolinecarboxylic acid hydrochloride

A procedure similar to Example 1 is used, wherein 1-cyclopropyl-1,4-dihydro-6,7-difluoro-8-methoxy-4-oxo-quinoline-3-carboxylic acid (precursor A ) And (5 (S) -ethyl-piperidin-3 (S) -yl) -carbamic acid tert-butyl ester (precursor N) are used as starting material. In this procedure, the same reaction conditions and molar ratio of reactants as in Example 1 are used.

Example 3

7- [3S-amino-5,5-dimethyl-piperidinyl] -1-cyclopropyl-1,4-dihydro-6-fluoro-8-methyl-4-oxo-3-quinolinecarboxylic acid Hydrochloride

1-cyclopropyl-1,4-dihydro-6,7-difluoro-8-methoxy-4-oxo-quinoline-3-carboxylic acid (precursor A) and (5,5-dimethyl-pi A procedure similar to Example 1 is used except that ferridin-3 (S) -yl) -carbamic acid tert-butyl ester (precursor O) is used as starting material. In this procedure, the same reaction conditions and molar ratio of reactants as in Example 1 are used.

Example 4

7- [3S-amino-4S-ethyl-5R-methyl-piperidinyl] -1-cyclopropyl-1,4-dihydro-6-fluoro-8-methoxy-4-oxo-3-quinolinecar Acid hydrochloride

1-cyclopropyl-1,4-dihydro-6,7-difluoro-8-methoxy-4-oxo-quinoline-3-carboxylic acid (precursor A) and 3 (S) -tert-butoxy A procedure similar to Example 1 is used except that carbonylamino-4 (R) -ethyl-5 (S) -methyl-piperidine (precursor L) is used as starting material. In this procedure, the same reaction conditions and molar ratio of reactants as in Example 1 are used.

Example 5

7- [7-amino-8R-methyl-5-azaspiro [2.5] -octanyl] -1-cyclopropyl-1,4-dihydro-6-fluoro-8-methoxy-4-oxo-3 -Quinolinecarboxylic acid hydrochloride

1-cyclopropyl-1,4-dihydro-6,7-difluoro-8-methoxy-4-oxo-quinoline-3-carboxylic acid (precursor A) and (8 (R) -methyl-5 A procedure similar to Example 1 is used except that aza-spiro [2.5] oct-7-yl) -carbamic acid tert-butyl ester (precursor Q) is used as starting material. In this procedure, the same reaction conditions and molar ratio of reactants as in Example 1 are used.

Example 6

7- [8-amino-6-azaspiro [3.5] -nonanyl] -1-cyclopropyl-1,4-dihydro-6-fluoro-8-methyl-4-oxo-3-quinolinecarboxylic acid Hydrochloride

1-cyclopropyl-1,4-dihydro-6,7-difluoro-8-methoxy-4-oxo-quinoline-3-carboxylic acid (precursor A) and (6-aza-spiro [3.5] A procedure similar to Example 1 is used except that non-8-yl) -carbamic acid tert-butyl ester (precursor P) is used as starting material. In this procedure, the same reaction conditions and molar ratio of reactants as in Example 1 are used.

Example 7

7- [3S-amino-5S-methyl-piperidinyl] -6-bromo-8-chloro-1-cyclopropyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid dihydrochloride

6-Bromo-8-chloro-1-cyclopropyl-1,4-dihydro-7-fluoro-4-oxoquinoline-3-carboxylic acid (precursor B) and (5 (S) -methyl-py A procedure similar to Example 1 is used except that ferridin-3 (S) -yl) -carbamic acid tert-butyl ester (precursor M) is used as starting material. In this procedure, the same reaction conditions and molar ratio of reactants as in Example 1 are used.

Example 8

7- [3S-amino-4R-ethyl-5S-methyl-piperidinyl] -6-bromo-8-chloro-1-cyclopropyl-1,4-dihydro-4-oxo-3-quinolinecar Acid hydrochloride

6-Bromo-8-chloro-1-cyclopropyl-1,4-dihydro-7-fluoro-4-oxoquinoline-3-carboxylic acid (precursor B) and 3 (S) -tert-butoxy A procedure similar to Example 1 is used except that carbonylamino-4 (R) -ethyl-5 (S) -methyl-piperidine (precursor L) is used as starting material. In this procedure, the same reaction conditions and molar ratio of reactants as in Example 1 are used.

Example 9

7- [3S-amino-5,5-dimethyl-4R-methyl-piperidinyl] -8-chloro-1-cyclopropyl-1,4-dihydro-6-methyl-4-oxo-3-quinoline Preparation of Carboxylic Acid Dihydrochloride

8-Chloro-1-cyclopropyl-1,4-dihydro-7-fluoro-6-methyl-4-oxo-quinoline-3-carboxylic acid boron difluoride complex

8-chloro-1-cyclopropyl-1,4-dihydro-7-fluoro-6-methyl-4-oxoquinoline-3-carboxylic acid (precursor C) (1 g, 3.4 mmol) was dissolved in THF (10 mL). ) And boron trifluoride etherate (1.76 mL, 13.9 mmol) is added. The mixture is stirred at 60 ° C. for 2 hours and then cooled to room temperature. The desired product is collected by filtration, washed and air dried.

7- [3S-tert-butoxycarbonylamino-5,5-dimethyl-4R-methyl-piperidinyl] -8-chloro-1-cyclopropyl-1,4-dihydro-6-methyl-4 Oxo-3-quinolinecarboxylic acid

8 -Chloro-1-cyclopropyl-1,4-dihydro-7-fluoro-6-methyl-4-oxo-quinoline-3-carboxylic acid boron difluoride complex (0.10 g, 0.291 mmol) was added 2 dissolved in mL of acetonitrile, followed by diisopropylethylamine (0.16 mL, 0.923 mmol) and 3 (S) -tert-butoxycarbonylamino-4 (R) -methyl-5,5-dimethyl-pi Ferridine (precursor R) (0.086 g, 0.353 g) is added. The mixture is stirred at 60 ° C. for 24 hours and then the solvent is removed by evaporation. The residue is dissolved in 5 mL of ethanol and 2 mL of triethylamine. The solution is stirred at 80 ° C. for 4 hours and then evaporated to dryness. The desired compound is isolated by flash chromatography on silica gel using EtOAc / hexanes.

7- [3S-amino-5,5-dimethyl-4R-methyl-piperidinyl] -8-chloro-1-cyclopropyl-1,4-dihydro-6-methyl-4-oxo-3-quinoline Carboxylic acid hydrochloride

7- [3S-tert-butoxycarbonylamino-5,5-dimethyl-4R-methyl-piperidinyl] -8-chloro-1-cyclopropyl-1,4-dihydro-6-methyl-4 Oxo-quinoline-3-carboxylic acid (0.54 g, 0.104 mmol) is dissolved in ethanol (2 mL) and concentrated hydrochloric acid (0.5 mL). After 0.5 h at room temperature, the mixture is cooled in an ice bath and the desired compound is collected by filtration.

Example 10

7- [3S-amino-4R-methyl-5S-methyl-piperidinyl] -8-chloro-1-cyclopropyl-6-hydroxy-1,4-dihydro-4-oxo-3-quinolinecarboxyl Acid dihydrogen sulfate

Ethyl 7- [3S-t-butoxycarbonylamino-4R-methyl-5S-methyl-piperidinyl] -8-chloro-1-cyclopropyl-1,4-dihydro-6-nitro-4-oxo 3-quinolinecarboxylate

Ethyl 8-chloro-1-cyclopropyl-1,4-dihydro-7-fluoro-6-nitro-4-oxo-quinoline-3-carboxylate (precursor D) (0.064 g, 0.180 mmol) and 3 (S) -tert-butoxycarbonylamino-4 (R) -methyl-5 (S) -methyl-piperidine (precursor S) (0.08 g, 0.351 mmol) was dissolved in DMSO (1 mL) and room temperature Stir for 15 minutes. Water (5 mL) is then added and the desired product is collected by filtration.

Ethyl 7- [3S-t-butoxycarbonylamino-4R-methyl-5S-methyl-piperidinyl] -6-amino-8-chloro-1-cyclopropyl-1,4-dihydro-4-oxo 3-quinolinecarboxylate

Ethyl 7- [3S-t-butoxycarbonylamino-4R-methyl-5S-methyl-piperidinyl] -8-chloro-1-cyclopropyl-1,4-dihydro-6-nitro-4-oxo 3-Quinolinecarboxylate (0.072 g, 0.128 mmol) is dissolved in ethanol (1 mL) and Raney nickel (0.035 g) is added. The reaction mixture is stirred for 18 h at room temperature under hydrogen (1 atm). The catalyst is removed by filtration on celite and the filtrate is evaporated to yield the desired product.

Ethyl 7- [3S-t-butoxycarbonylamino-4R-methyl-5S-methyl-piperidinyl] -8-chloro-1-cyclopropyl-6-hydroxy-1,4-dihydro-4- Oxo-3-quinolinecarboxylate

Ethyl 7- [3S-t-butoxycarbonylamino-4R-methyl-5S-methyl-piperidinyl] -6-amino-8-chloro-1-cyclopropyl-1,4-dihydro- at 0 ° C 4-oxo-3-quinolinecarboxylate (0.068 g, 0.127 mmol) is dissolved in 2N HCl (2 mL). Then a solution of sodium nitrite (0.01 g, 0.145 mmol) in water (0.2 mL) is added and the solution is stirred at 0 ° C. for 1 hour. A solution of NaBF ₄ (0.02 g, 0.182 mmol) in water (0.2 mL) is added and the resulting precipitate is filtered off. The solid is resuspended in trifluoroacetic acid (0.2 mL) and K ₂ CO ₃ (0.5 g) is added in portions at 40 ° C. Water (10 mL) is added and the reaction mixture is stirred at rt for 2 h. The aqueous phase is extracted with dichloromethane and the desired product is purified by chromatography on silica gel using 5% methanol in CH ₂ Cl ₂ as eluent.

7- [3S-amino-4R-methyl-5S-methyl-piperidinyl] -8-chloro-1-cyclopropyl-6-hydroxy-1,4-dihydro-4-oxo-3-quinolinecarboxyl Acid dihydrogen sulfate

Ethyl 7- [3S-t-butoxycarbonylamino-4R-methyl-5S-methyl-piperidinyl] -8-chloro-1-cyclopropyl-6-hydroxy-1,4-dihydro-4- Oxo-3-quinolinecarboxylate (0.042 g, 0.079 mmol) is suspended in a mixture of acetic acid / sulfuric acid / water (6: 4: 1, 1 mL) and the reaction mixture is heated at reflux for 4 h. After cooling, the desired product is isolated by filtration.

Example 11

7- [3S-amino-5S-methyl-piperidinyl] -1-cyclopropyl-1,4-dihydro-6-fluoro-4-oxo-1,8-naphthyridine-3-carboxylic acid hydrochloride

Ethyl-7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-naphthyridine-3-carboxylate (precursor E) (0.062 g, 0.200 mmol), (5 ( S) -Methyl-piperidin-3 (S) -yl) -carbamic acid tert-butyl ester (precursor M) (0.048 g, 0.214 mmol) and triethylamine (0.05 mL, 0.359 mmol) were acetonitrile (1 mL) and stirred at room temperature for 18 hours. The solvent is evaporated in vacuo and the residue is crystallized in water. The resulting solid is collected by filtration and suspended in a 1/1 mixture of 1N NaOH and ethanol (1 mL) and stirred at room temperature for 24 hours. The pH is then adjusted to 7.4 with 1N HCl and the precipitate is collected by filtration. The solid is resuspended in ethanol and treated with 6N hydrochloric acid for 18 hours at room temperature. The desired final product is collected by filtration.

Example 12

7- [3S-amino-4S-ethyl-5R-methyl-piperidinyl] -1-cyclopropyl-1,4-dihydro-6-fluoro-4-oxo-1,8-naphthyridine-3- Carboxylic acid hydrochloride

A procedure similar to Example 11 above is used, with ethyl-7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-naphthyridine-3-carboxylate (precursor E) And 3 (S) -tert-butoxycarbonylamino-4 (R) -ethyl-5 (S) -methyl-piperidine (precursor L) is used as starting material. This procedure uses the same reaction conditions and molar ratios of reactants as in Example 11.

Example 13

7- [3S-amino-5S-methyl-piperidinyl] -9-fluoro-2,3-dihydro-3S-methyl-7-oxo-7H-pyrido [1,2,3-dec]- 1,4-benzoxazine-6-carboxylic acid hydrochloride.

9,10-difluoro-2,3-dihydro-3S-methyl-7-oxo-7H-pyrido [1,2,3-de] -1,4-benzoxazine-6-carboxylic acid ( Precursor F) (0.056 g, 0.199 mmol), (5 (S) -methyl-piperidin-3 (S) -yl) -carbamic acid tert-butyl ester (precursor M) (0.045 g, 0.201 mmol) and tri Ethylamine (0.075 mL, 0.538 mmol) is dissolved in N-methyl-pyrrolidone (1 mL). The solution is stirred at 80 ° C. for 18 hours and poured into an ice / water mixture. The pH is reduced to 2 with dilute HCl and the resulting precipitate is collected by filtration. The solid is suspended in ethanol and 6N HCl is added. After 18 hours at room temperature, the desired product is collected by filtration and air dried.

Example 14

7- [3S-amino-5,5-dimethyl-piperidinyl] -9-fluoro-2,3-dihydro-3S-methyl-7-oxo-7H-pyrido [1,2,3- De] -1,4-benzoxazine-6-carboxylic acid hydrochloride.

A procedure similar to Example 13 was used, wherein 9,10-difluoro-2,3-dihydro-3S-methyl-7-oxo-7H-pyrido [1,2,3-dec] -1, 4-benzoxazine-6-carboxylic acid (precursor F) and (5,5-dimethyl-piperidin-3 (S) -yl) -carbamic acid tert-butyl ester (precursor O) as starting material do. This procedure uses the same reaction conditions and molar ratios of reactants as in Example 13.

Example 15

7- [7-amino-8R-methyl-5-azaspiro [2.5] -octanyl] -5,6,8-trifluoro-9-cyclopropyl-1,3,4,9-tetra-hydroiso Thiazolo [5,4-b] quinoline-3,4-dione hydrochloride

5,6,7,8-tetrafluoro-9-cyclopropyl-1,3,4,9-tetrahydroisothiazolo [5,4-b] quinoline-3,4-dione (precursor G) ( 0.067 g, 0.203 mmol) is suspended in DMF (1 mL) and (8 (R) -methyl-5-aza-spiro [2.5] oct-7-yl) -carbamic acid tert-butyl ester (precursor Q) ( 0.051 g, 0.212 mmol) and triethylamine (0.05, 0.359 mmol mL) are added. The reaction mixture is stirred at 50 ° C. for 6 hours. The mixture is concentrated in vacuo and the residue is triturated with water. The precipitate is collected, rinsed with ethanol and suspended in ethanol. A drop of 12N HCl is added and the suspension is stirred at 20 ° C. for 12 hours. The desired product is collected by filtration and air dried.

Example 16

7- [3S-amino-5S-ethyl-piperidinyl] -5,6,8-trifluoro-9-cyclopropyl-1,3,4,9-tetrahydroiso-thiazolo [5,4- b] quinoline-3,4-dione hydrochloride

A procedure similar to Example 15 is used, with 5,6,7,8-tetrafluoro-9-cyclopropyl-1,3,4,9-tetrahydroisothiazolo [5,4-b] quinoline- 3,4-dione (precursor G) and (5 (S) -ethyl-piperidin-3 (S) -yl) -carbamic acid tert-butyl ester (precursor N) are used as starting materials. This procedure uses the same reaction conditions and molar ratios of reactants as in Example 15.

Example 17

Preparation of 8- [3S-amino-5S-methyl-piperidinyl] -1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid hydrochloride

Ethyl 8- [3S-t-butoxycarbonylamino-5S-methyl-piperidinyl] -1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carbox Carboxylate

Et ₃ N (0.034 mL, 0.244 mmol), (5 (S) -methyl-piperidin-3 (S) -yl) -carbamic acid tert-butyl ester (precursor M) in DMF (2 mL) (0.033 g) , 0.149 mmol) and ethyl 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (precursor H) (0.040 g, 0.124 mmol) The solution of is stirred for 3 days at room temperature. The solvent is evaporated under reduced pressure. The residue is dissolved in CH ₂ Cl ₂ , the solution is washed with 0.1 M HCl, dried over anhydrous MgSO ₄ and concentrated to give the desired product.

8- [3S-t-butoxycarbonylamino-5S-methyl-piperidinyl] -1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxyl Acid trifluoroacetate

16% NaOH (0.15 mL) and ethyl 8- [3S-t-butoxycarbonylamino-5S-methyl-piperidinyl] -1-cyclopropyl-7-fluoro-9-methyl in EtOH (2 mL) A solution of -4-oxo-4H-quinolizine-3-carboxylate (0.060 g, 0.120 mmol) is stirred at room temperature for 6 hours. This mixture is partitioned between CH ₂ Cl ₂ and 0.1 N HCl solution. The organic layer is separated and the aqueous layer is extracted with CH ₂ Cl ₂ (twice). The combined extracts are dried over anhydrous MgSO ₄ and evaporated to afford a yellow solid which is purified by preparative reverse phase HPLC using a CH ₃ CN / H ₂ O—0.1% TFA gradient as eluent. The fraction containing the product is concentrated to give the desired product.

8- [3S-amino-5S-methyl-piperidinyl] -1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid hydrochloride

8- [3S-t-butoxycarbonylamino-5S-methyl-piperidin-1-yl] -1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine- 3-carboxylic acid trifluoroacetate (0.032 g, 0.055 mmol) is treated with concentrated HCl (0.5 mL) for 10 minutes at room temperature. The volatiles are evaporated under reduced pressure to give the desired product.

Example 18

8- [3S-amino-5S-ethyl-piperidinyl] -1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid dihydrochloride

A procedure similar to Example 17 above is used, with ethyl 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (precursor H) and (5 (S) -Ethyl-piperidin-3 (S) -yl) -carbamic acid tert-butyl ester (precursor N) is used as starting material. This procedure uses the same reaction conditions and molar ratios of reactants as in Example 17.

Example 19

Preparation of 8- [3S-amino-5S-ethyl-piperidinyl] -1-cyclopropyl-7-hydroxy-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid dihydrochloride

Ethyl 8- [3S-t-butoxycarbonylamino-5S-ethyl-piperidinyl] -1-cyclopropyl-9-methyl-7-nitro-4-oxo-4H-quinolizine-3-carboxyl Rate

Et ₃ N (0.041 mL, 0.294 mmol), (5 (S) -ethyl-piperidin-3 (S) -yl) -carbamic acid tert-butyl ester (precursor N) (0.035 g) in DMF (2 mL) , 0.153 mmol) and ethyl 8-chloro-1-cyclopropyl-9-methyl-7-nitro-4-oxo-4H-quinolizine-3-carboxylate (precursor I) (0.053 g, 0.151 mmol) The solution is stirred for 3 days at room temperature. The solvent is evaporated under reduced pressure. The residue is dissolved in CH ₂ Cl ₂ , the solution is washed with 0.1 M HCl, dried over anhydrous MgSO ₄ and concentrated to give the desired product.

Ethyl 8- [3S-t-butoxycarbonylamino-5S-ethyl-piperidinyl] -7-amino-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxyl Rate

Ethyl 8- [3S-t-butoxycarbonylamino-5S-ethyl-piperidinyl] -1-cyclopropyl-9-methyl-7-nitro-4-oxo-4H-quinolizine-3-carboxyl Rate (0.065 g, 0.120 mmol) is dissolved in ethanol (1 mL) and Raney nickel (0.035 g) is added. The reaction mixture is stirred for 18 h at room temperature under hydrogen (1 atm). The catalyst is removed by filtration on celite and the filtrate is evaporated to give the desired product.

Ethyl 8- [3S-t-butoxycarbonylamino-5S-ethyl-piperidinyl] -1-cyclopropyl-7-hydroxy-9-methyl-4-oxo-4H-quinolizine-3-carbox Carboxylate

Ethyl 8- [3S-t-butoxycarbonylamino-5S-ethyl-piperidinyl] -7-amino-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3 at 0 ° C -Carboxylate (0.062 g, 0.120 mmol) is dissolved in 2N HCl (2 mL). Then a solution of sodium nitrite (0.009 g, 0.130 mmol) in water (0.2 mL) is added and the solution is stirred at 0 ° C. for 1 h. A solution of NaBF ₄ (0.02 g, o 182 mmol) in water (0.2 mL) is added and the resulting precipitate is filtered off. The solid is resuspended in trifluoroacetic acid (0.2 mL) and K ₂ CO ₃ (0.5 g) is added in portions at 40 ° C. Water (10 mL) is added and the reaction mixture is stirred at rt for 2 h. The aqueous phase is extracted with CH ₂ Cl ₂ and the desired product is purified by flash chromatography on silica gel using 5% methanol in CH ₂ Cl ₂ as eluent.

8- [3S-t-butoxycarbonylamino-5S-ethyl-piperidinyl] -1-cyclopropyl-7-hydroxy-9-methyl-4-oxo-4H-quinolizine-3-carboxyl mountain

16% NaOH (0.15 mL) and ethyl 8- [3S-t-butoxycarbonylamino-5S-methyl-piperidinyl] -1-cyclopropyl-7-hydroxy-9-methyl in EtOH (2 mL) A solution of -4-oxo-4H-quinolizine-3-carboxylate (0.036 g, 0.070 mmol) is stirred at room temperature for 6 hours. This mixture is partitioned between CH ₂ Cl ₂ and 0.1 N HCl solution. The organic layer is separated and the aqueous layer is extracted with CH ₂ Cl ₂ (twice). The combined extracts are dried over anhydrous MgSO ₄ and evaporated to afford the desired product.

8- [3S-amino-5S-ethyl-piperidinyl] -1-cyclopropyl-7-hydroxy-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid dihydrochloride

8- [3S-t-butoxycarbonylamino-5S-methyl-piperidin-1-yl] -1-cyclopropyl-7-hydroxy-9-methyl-4-oxo-4H-quinolizine- 3-carboxylic acid (0.031 g, 0.063 mmol) is treated with concentrated HCl (0.5 mL) at room temperature for 10 minutes. The volatiles are evaporated under reduced pressure to give the desired product.

Example 20

Preparation of 7- [3S-amino-5S-methyl-piperidinyl] -3-amino-8-chloro-1-cyclopropyl-6-fluoro-1H-quinazolin-2,4-dione hydrochloride

{7- [3S-t-butoxycarbonylamino-5S-methyl-piperidin-1-yl) -8-chloro-1-cyclopropyl-6-fluoro-2,4-dioxo-1, 4-dihydro-2H-quinazolin-3-yl} carbamic acid tert-butyl ester

8-chloro-1-cyclopropyl-6,7-difluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl) carbamic acid tert-butyl ester (precursor J) (0.06 g, 0.155 mmol), (5 (S) -methyl-piperidin-3 (S) -yl) -carbamic acid tert-butyl ester (precursor M) (0.66 g, 0.310 mmol), and triethylamine The solution of (0.065 mL, 0.465) is stirred and heated for 48 h under reflux in acetonitrile (3 mL). After cooling to room temperature, the reaction mixture is diluted with ethyl acetate and washed with saturated NaHCO ₃ , water and brine. The organic layer is dried over MgSO ₄ , filtered and concentrated. The resulting residue is purified by flash chromatography on silica gel using EtOAc / hexanes to afford the desired product.

7- [3S-amino-5S-methyl-piperidinyl] -3-amino-8-chloro-1-cyclopropyl-6-fluoro-1H-quinazolin-2,4-dione hydrochloride

Hydrogen chloride gas is bubbled into CH ₂ Cl _{2 for} 15 minutes. The resulting solution was then cooled to 0 ° C. and {7- [3S-amino-5S-methyl-piperidin-1-yl) -8-chloro-1- cyclopropyl-6-fluoro-2,4-di To a solution of oxo-1,4-dihydro-2H-quinazolin-3-yl} carbamic acid tert-butyl ester (0.067 g, 0.115 mmol) is added. The resulting mixture is allowed to slowly warm up to room temperature. After 30 hours, the precipitate is filtered off, washed with CH ₂ Cl ₂ and hexanes and dried under vacuum to afford the desired product.

Example 21

7- [3S-amino-4R-ethyl-5S-methyl-piperidinyl] -3-amino-8-chloro-1-cyclopropyl-6-fluoro-1H-quinazolin-2,4-dione hydrochloride

A procedure similar to Example 20 is used, with 8-chloro-1-cyclopropyl-6,7-difluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl. Carbamic acid tert-butyl ester (precursor J) and 3 (S) -tert-butoxycarbonylamino-4 (R) -ethyl-5 (S) -methyl-piperidine (precursor L) as starting material use. In this procedure, the same reaction conditions and molar ratios of the reactants as in Example 20 are used.

Example 22

Preparation of 7- [3S-amino-5S-methyl-piperidinyl] -3-amino-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazolin-2,4-dione hydrochloride

7- [3S-t-butoxycarbonylamino-5S-methyl-piperidinyl) -3-amino-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazolin-2,4- ion

Triethylamine (0.084 mL, 0.600 mmol) and 3-amino-1-cyclopropyl-6,7-difluoro-8-methyl-1H-quinazolin-2,4-dione in acetonitrile (3 mL) (5 (S) -Methyl-piperidin-3 (S) -yl) -carbamic acid tert-butyl ester (precursor M) (0.088 g, 0.412 mmol) in a solution of (precursor K) (0.055 g, 0.206 mmol) Add). The solution is heated under reflux for 18 h, the solvent is removed under reduced pressure and the residue is triturated with water. The solid is collected by filtration and air dried to afford the desired product.

7- [3S-amino-5S-methyl-piperidinyl) -3-amino-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazolin-2,4-dione hydrochloride

Hydrogen chloride gas is bubbled into CH ₂ Cl _{2 for} 15 minutes. The resulting solution was then cooled to 0 ° C. and 7- [3S-t-butoxycarbonylamino-5S-methyl-piperidinyl) -3-amino-1-cyclopropyl-6-fluoro-8-methyl- To a solution of 1H-quinazolin-2,4-dione (0.070 g, 0.145 mmol). The resulting mixture is allowed to slowly warm up to room temperature. After 30 hours, the precipitate is filtered off, washed with CH ₂ Cl ₂ and hexanes and dried under vacuum to afford the desired product.

Example 23

7- [3S-amino-4R-methyl-5,5-dimethyl-piperidinyl] -3-amino-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazolin-2,4- Dione hydrochloride

A procedure similar to Example 22 was used, using 3-amino-1-cyclopropyl-6,7-difluoro-8-methyl-1H-quinazolin-2,4-dione (precursor K) and 3 ( S) -tert-butoxycarbonylamino-4 (R) -methyl-5,5-dimethyl-piperidine (precursor R) is used as starting material. In this procedure the same reaction conditions and molar ratios of reactants as in Example 22 are used.

VII. Example-Compositions and Methods of Use

The following non-limiting examples illustrate the compositions and methods of use of the present invention.

Example 16

A tablet composition for oral administration according to the invention is prepared, which contains:

ingredient amount Compound of Example 1 150 mg Lactose 120 mg Corn starch 70 mg talc 4 mg Magnesium stearate 1 mg

Other compounds having the structure according to formula (I) are used, which results in substantially similar results.

Example 17

A capsule for oral administration containing 200 mg of the active agent according to the invention is prepared, which contains:

ingredient Volume (% w / w) Compound of Example 4 15% Function lactose 43% Microcrystalline Cellulose 33% Crosspovidon 3.3% Magnesium stearate 5.7%

Other compounds having the structure according to formula (I) are used, which results in substantially similar results.

Example 18

A saline based composition for ophthalmic administration according to the present invention is prepared, which contains:

ingredient Volume (% w / w) Compound of Example 7 10% Saline 90%

Other compounds having the structure according to formula (I) are used, which results in substantially similar results.

Example 19

To prepare an intranasal composition for topical administration according to the invention, which contains:

ingredient Composition (% w / v) Compound of Example 10 0.20 Benzalkonium chloride 0.02 EDTA 0.05 glycerin 2.0 PEG 1450 2.0 air freshener 0.075 Purified water A reasonable amount

Other compounds having the structure according to formula (I) are used, which results in substantially similar results.

Example 20

An inhalable aerosol composition according to the invention is prepared, which contains:

ingredient Composition (% w / v) Compound of Example 14 5.0 Ascorbic acid 0.1 menthol 0.1 Sodium saccharin 0.2 Propellant (F12, F114) A reasonable amount

Other compounds having the structure according to formula (I) are used, which results in substantially similar results.

Example 21

A topical ophthalmic composition according to the invention is prepared, which contains:

ingredient Composition (% w / v) Compound of Example 15 0.10 Benzalkonium chloride 0.01 EDTA 0.05 Hydroxyethyl cellulose 0.5 Acetic acid 0.20 Sodium metabisulfite 0.10 Sodium Chloride (0.9%) A reasonable amount

Other compounds having the structure according to formula (I) are used, which results in substantially similar results.

Example 22

An antimicrobial composition for parenteral administration according to the invention is prepared, which contains:

ingredient amount Compound of Example 12 30 mg / mL excipient Excipients: PH 5 lecithin-containing buffer buffered with 50 mm phosphate 0.48% Carboxymethyl Cellulose 0.53 Povidone 0.50 Methyl paraben 0.11 Profile paraben 0.011

The components are mixed to form a suspension. Approximately 2.0 mL of suspension is administered intramuscularly to human subjects suffering from lower respiratory tract infections with Streptococcus pneumoniae. This administration is repeated twice daily for approximately 14 days. After four days, the symptoms of the disease subside, indicating that the pathogen has been substantially eradicated. Use of other compounds having a structure according to formula (I) results in substantially similar results.

Example 23

An enteric coated antimicrobial composition for oral administration according to the present invention is prepared, which contains the following core tablets:

ingredient Amount (mg) Compound of Example 5 350.0 Maltodextrin 30.0 Magnesium stearate 5.0 Microcrystalline Cellulose 100.0 Colloidal silicon dioxide 2.5 Povidone 12.5

The ingredients are mixed into the bulk mixture. Compressed tablets are formed using tableting methods known in the art. The tablets are then coated with a suspension of methacrylic acid / methacrylic acid ester polymer in isopropanol / acetone. Two tablets are administered orally every 8 hours for 4 days to a subject with a urinary tract infection with Escherichia coli. The symptoms of the disease then subside, indicating that the pathogen has been substantially eradicated. Use of other compounds having a structure according to formula (I) results in substantially similar results.

All documents cited in the Detailed Description of the Invention are incorporated herein by reference in their entirety, and citation of any document should not be construed as an admission that this document is a prior art relating to the present invention.

While particular embodiments of the invention have been described, it will be apparent to those skilled in the art that various changes and modifications of the invention can be made without departing from the spirit and scope of the invention. It is intended that the appended claims cover all such modifications as fall within the scope of the invention.

Claims (10)

A compound having a structure according to formula (I), or an optical isomer, diastereomer or enantiomer thereof; Pharmaceutically acceptable salts, hydrates, or biohydrolyzable esters, amides or imides thereof: [Formula I] (I) (here, (A) (1) A ¹ is selected from -N- and -C (R ⁸ )-, R ⁸ is hydrogen, halo, C ₁ to about C ₆ alkyl, C ₂ to about C ₆ alkene or alka Phosphorus and C ₁ to about C ₆ alkoxy, all such alkyl, alkene, alkane and alkoxy moieties being unsubstituted or substituted with 1 to about 3 fluoro;    (2) a, b and c are each independently a single or double bond;    (3) (a) X is -C- or -N-; (i) when X is -C-, a is a double bond and b is a single bond, and (ii) when X is -N-, a is a single bond and b is a double bond; (b) Y is selected from -N (R ¹ )-and -CR ° R ^1- ; R ° is hydrogen or absent, when b is a single bond, R ° is hydrogen and when b is a double bond, R ° is absent; (c) Z is selected from -C (COR ³ )-, -N (R ³ )-and -N (NHR ³ )-; (i) when Z is -C (COR ³ )-, c is a double bond; (ii) when Z is -N (R ³ )-or -N (NHR ³ )-, c is a single bond; ; (d) provided that Y is -N (R ¹ )-only when X is -C-; (e) Y is -C (R ¹ )-only when X is -N- and Z is -C (COR ³ )-; (f) Z is -N (R ³ )-or -N (NHR ³ )-only if X is -C-, Y is -N (R ¹ )-and A ¹ is -C (R ⁸ )-. One of; (4) R ¹ is C ₃ to about C ₆ cycloalkyl, C ₃ to about C ₆ heterocycloalkyl, C ₁ to about C ₆ alkyl, C ₂ to about C ₆ alkene or alkane, C ₁ To about C ₆ alkyloxy, 6-membered aryl and 6-membered heteroaryl, all such alkyl, alkenes, alkanes, alkoxy, cycloalkyl, aryl and heteroaryl are unsubstituted or substituted with 1 to 3 fluoro All such aryl and heteroaryl are also unsubstituted or substituted with one hydroxy at the 4-position; (5) R ² is hydrogen, double bond oxygen, C ₁ to about C ₆ alkyl, C ₂ to about C ₆ alkene or alkane, C ₁ to about C ₆ alkoxy and C ₁ to about C ₆ thio Selected from alkyl, provided that R ² is double bond oxygen only when Z is —N (OH) — or —N (NHR ³ ) —; (6) R ³ is hydrogen, hydroxy, C ₁ to about C ₆ alkyl, C ₂ to about C ₆ alkene or alkane, C ₁ to about C ₆ alkoxy and C ₁ to about C ₆ thioalkyl Is selected from; (7) R ⁵ is selected from hydrogen, hydroxy, amino, halo, alkoxy of C ₁ to about C ₆ alkyl, C ₂ to about C ₄ alkene, or alkyne, and C ₁ to about C _4, all of these Alkyl, alkene, alkane and alkoxy moieties are unsubstituted or substituted with 1 to 3 fluoro; (8) R ⁶ is selected from hydroxy, aminocarbonyl, fluoro, chloro, bromo, cyano, alkyl of C ₁ to about C ₂ and alkenyl or alkynyl of C ₂ to about C ₄ , All such alkyl, alkenyl and alkynyl moieties are unsubstituted or substituted with from 1 to about 3 fluoro; (9) R ⁷ and R ^{7 '} are each independently (a) hydrogen, C ₁ to about C ₆ alkyl, C ₂ to about C ₆ alkene or alkane, C ₁ to about C ₆ alkoxy, C ₁ to about C ₆ alkylthio and C ₁ to about C ₆ is selected from heteroalkyl, provided that R ⁷ and R ^{7 '} are not both hydrogen; (b) R ⁷ and R ^{7 '} combine to form a C ₃ to about C ₆ cycloalkyl or heterocyclic ring comprising the carbon atoms to which they are attached;       (c) all such alkyl, alkene, alkane, alkoxy, alkylthio, heteroalkyl, cycloalkyl and heterocyclic moieties are unsubstituted or substituted with 1 to 3 fluoro; (10) R ⁹ and R ^{9 '} are each independently selected from hydrogen and C ₁ to about C ₃ alkyl, or R ⁹ and R ^9' are C ₃ to about C ₆ containing a nitrogen atom to which they are bonded To form a heterocyclic ring of; (11) R ¹⁰ represents a moiety on a piperidine ring other than R ⁷ , R ^{7 ′} and —NR ⁹ R ^{9 ′} , wherein each R ¹⁰ is independently hydrogen, alkyl of C ₁ to about C ₆ , C ₂ to about C ₆ alkene or alkane, C ₁ to about C ₆ alkoxy and C ₃ -C ₆ cycloalkyl, all such alkyl, alkene, alkane, alkoxy and cycloalkyl moieties are unsubstituted or To 3 fluoro; (B) when A ¹ is -C (R ⁸ )-, X is -C- and Y is -N (R ¹ )-, R ⁸ and R ¹ can be joined to form a 6-membered heterocyclic ring Where R ² , R ³ , R ⁵ , R ⁶ , R ⁷ , R ^{7 '} , R ⁹ , R ^{9 '} and R ¹⁰ are as described in (A); (C) If A ¹ is -C (R ⁸ )-, X is -C-, Y is -N (R ¹ )-and Z is -C (COR ³ ), then R ¹ and R ² are bonded to mono Can form a click or bicyclic heterocyclic ring, wherein R ³ , R ⁵ , R ⁶ , R ⁷ , R ^{7 ′} , R ⁸ , R ⁹ , R ^{9 '} and R ¹⁰ are as described in (A); (D) If A ¹ is -C (R ⁸ )-, X is -C-, Y is -N (R ¹ )-and Z is -C (COR ³ ), then R ² and R ³ are bonded to carbonyl To a 5-membered heterocycloalkyl substituted with a moiety, wherein R ¹ , R ⁵ , R 6, R ⁷ , R ^{7 ′} , R ⁸ , R ⁹ , R ^{9 '} and R ¹⁰ are as described in (A)). A compound according to claim 1 having a structure according to formula II: [Formula II] (II) (here, (A) (1) A ¹ is selected from -N- and -C (R ⁸ )-, R ⁸ is hydrogen, halo, C ₁ to about C ₆ alkyl, C ₂ to about C ₆ alkene or alka Phosphorus and C ₁ to about C ₆ alkoxy, all such alkyl, alkene, alkane and alkoxy moieties being unsubstituted or substituted with 1 to 3 fluoro; (2) R ¹ is C ₃ to about C ₆ cycloalkyl, C ₃ to about C ₆ heterocycloalkyl, C ₁ to about C ₆ alkyl, C ₂ to about C ₆ alkene or alkane, 6- And all such alkyl, cycloalkyl, aryl and heteroaryl are unsubstituted or substituted with 1 to 3 fluoro, all such aryl and heteroaryl are also unsubstituted or 4-position Is substituted with one hydroxy in; (3) R ² is hydrogen; (4) R ³ is hydroxy; (5) R ⁵ is selected from hydrogen, hydroxy, amino, halo, C ₁ to about C ₄ alkyl, C ₂ to about C ₄ alkene or alkane and C ₁ to about C ₄ alkoxy; All such alkyl, alkenyl, alkynyl and alkoxy moieties are unsubstituted or substituted with from 1 to about 3 fluoro; (6) R ⁶ is selected from hydroxy, fluoro, chloro, bromo, alkyl of C ₁ to about C ₂ and alkenyl or alkynyl of C ₂ to about C ₄ , all such alkyl, alkenyl and The alkynyl moiety is unsubstituted or substituted with from 1 to about 3 fluoro; (7) R ⁷ and R ^{7 '} are each independently (a) hydrogen, C ₁ to about C ₆ alkyl, C ₂ to about C ₆ alkene or alkane, C ₁ to about C ₆ alkoxy, C ₁ to about C ₆ alkylthio and C ₁ to about C ₆ is selected from heteroalkyl, provided that R ⁷ and R ^{7 '} are not both hydrogen; (b) R ⁷ and R ^{7 '} combine to form a C ₃ to about C ₆ cycloalkyl or heterocyclic ring comprising the carbon atoms to which they are attached;       (c) all such alkyl, alkene, alkane, alkoxy, alkylthio, heteroalkyl, cycloalkyl and heterocyclic moieties are unsubstituted or substituted with 1 to 3 fluoro; (8) R ¹⁰ is selected from C ₁ to about C ₆ alkyl, C ₂ to about C ₆ alkene or alkane and C ₁ to about C ₆ alkoxy, all such alkyl, alkene, alkane and alkoxy moieties Is unsubstituted or substituted with 1 to 3 fluoro; (B) R ⁸ and R ¹ combine to form a 6-membered heterocyclic ring wherein R ⁵ , R ⁶ , R ^{7 '} , R ⁷ , R ¹⁰ are as described in part (A)). A compound according to claim 1 having a structure according to formula III: [Formula III] (III) (here, (A) (1) R ⁸ is selected from hydrogen, halo, C ₁ to about C ₆ alkyl, C ₂ to about C ₆ alkene or alkane and C ₁ to about C ₆ alkoxy, all such alkyl, Alkene, alkane and alkoxy moieties are unsubstituted or substituted with 1 to 3 fluoro; (2) R ¹ is C ₃ to about C ₆ cycloalkyl, C ₃ to about C ₆ heterocycloalkyl, C ₁ to about C ₆ alkyl, C ₁ to about C ₆ alkenes, 6-membered aryl and Selected from 6-membered heteroaryl, all such alkyl, cycloalkyl, aryl and heteroaryl are unsubstituted or substituted with 1 to 3 fluoro, all such aryl and heteroaryl are also unsubstituted or in the 4-position Substituted with hydroxy of; (3) R ² is hydrogen; (4) R ³ is hydroxy; (5) R ⁵ is selected from hydrogen, hydroxy, amino, halo, C ₁ to about C ₄ alkyl, C ₂ to about C ₄ alkene or alkane and C ₁ to about C ₄ alkoxy, all of The alkyl, alkenyl, alkynyl and alkoxy moieties are unsubstituted or substituted with from 1 to about 3 fluoro; (6) R ⁶ is selected from hydroxy, fluoro, chloro, bromo, alkyl of C ₁ to about C ₂ and alkenyl or alkynyl of C ₂ to about C ₄ , all such alkyl, alkenyl and The alkynyl moiety is unsubstituted or substituted with from 1 to about 3 fluoro; (7) R ⁷ and R ^{7 '} are each independently (a) hydrogen, C ₁ to about C ₆ alkyl, C ₂ to about C ₆ alkene or alkane, C ₁ to about C ₆ alkoxy, C ₁ to about C ₆ alkylthio and C ₁ to about C ₆ is selected from heteroalkyl, provided that R ⁷ and R ^{7 '} are not both hydrogen; (b) R ⁷ and R ^{7 '} combine to form a C ₃ to about C ₆ cycloalkyl or heterocyclic ring comprising the carbon atoms to which they are attached;       (c) all such alkyl, alkene, alkane, alkoxy, alkylthio, heteroalkyl, cycloalkyl and heterocyclic moieties are unsubstituted or substituted with 1 to 3 fluoro; (8) R ¹⁰ is selected from C ₁ to about C ₆ alkyl, C ₂ to about C ₆ alkene or alkane and C ₁ to about C ₆ alkoxy, all such alkyl, alkene, alkane and alkoxy moieties Is unsubstituted or substituted with 1 to 3 fluoro). A compound according to claim 1 having a structure according to formula IV: [Formula IV] (IV) (here, (A) (1) R ⁸ is selected from hydrogen, halo, C ₁ to about C ₆ alkyl, C ₂ to about C ₆ alkene or alkane and C ₁ to about C ₆ alkoxy, all such alkyl, Alkene, alkane and alkoxy moieties are unsubstituted or substituted with 1 to 3 fluoro; (2) R ¹ is C ₃ to about C ₆ cycloalkyl, C ₃ to about C ₆ heterocycloalkyl, C ₁ to about C ₆ alkyl, C ₁ to about C ₆ alkenes, 6-membered aryl and Selected from 6-membered heteroaryl, all such alkyl, cycloalkyl, aryl and heteroaryl are unsubstituted or substituted with 1 to 3 fluoro, all such aryl and heteroaryl are also unsubstituted or in the 4-position Substituted with hydroxy of; (3) Z is either -N (R ³ )-or -N (NHR ³ )-; (4) R ³ is selected from hydrogen, hydroxy and alkyl of C ₁ to about C ₆ ; (5) R ⁵ is selected from hydrogen, hydroxy, amino, halo, C ₁ to about C ₄ alkyl, C ₂ to about C ₄ alkene or alkane and C ₁ to about C ₄ alkoxy, all of The alkyl, alkenyl, alkynyl and alkoxy moieties are unsubstituted or substituted with from 1 to about 3 fluoro; (6) R ⁶ is selected from hydroxy, fluoro, chloro, bromo, alkyl of C ₁ to about C ₂ and alkenyl or alkynyl of C ₂ to about C ₄ , all such alkyl, alkenyl and The alkynyl moiety is unsubstituted or substituted with from 1 to about 3 fluoro; (7) R ⁷ and R ^{7 '} are each independently (a) hydrogen, C ₁ to about C ₆ alkyl, C ₂ to about C ₆ alkene or alkane, C ₁ to about C ₆ alkoxy, C ₁ to about C ₆ alkylthio and C ₁ to about C ₆ is selected from heteroalkyl, provided that R ⁷ and R ^{7 '} are not both hydrogen; (b) R ⁷ and R ^{7 '} combine to form a C ₃ to about C ₆ cycloalkyl or heterocyclic ring comprising the carbon atoms to which they are attached;       (c) all such alkyl, alkene, alkane, alkoxy, alkylthio, heteroalkyl, cycloalkyl and heterocyclic moieties are unsubstituted or substituted with 1 to 3 fluoro; (8) R ¹⁰ is selected from C ₁ to about C ₆ alkyl, C ₂ to about C ₆ alkene or alkane and C ₁ to about C ₆ alkoxy, all such alkyl, alkene, alkane and alkoxy moieties Is unsubstituted or substituted with 1 to 3 fluoro). The compound of claim 1, wherein R ⁶ is selected from hydroxy, fluoro, bromo, chloro and methyl. 6. The compound of claim 1, wherein R ^{7 ′} is hydrogen, R ⁷ is selected from methoxy, thiomethoxy, methyl and ethyl, and all such methoxy, thiomethoxy, methyl and ethyl Wherein the moiety is unsubstituted or substituted with from 1 to about 3 fluoro. The method according to any one of claims 1 to 5, (a) R ⁷ is methyl and the carbon atom piperidine ring member to which R ⁷ is attached is S-coordinated; (b) R ⁹ and R ^{9 '} are both hydrogen and the carbon atom piperidine ring member to which -NR ⁹ R ^9' is attached is S-coordinated. The method of claim 1, 7- [3S-amino-5S-methyl-piperidinyl] -1-cyclopropyl-1,4-dihydro-6-fluoro-8-methoxy-4-oxo-3-quinolinecarboxylic acid; 7- [3S-amino-5R-methyl-piperidinyl] -1-cyclopropyl-1,4-dihydro-6-fluoro-8-methoxy-4-oxo-3-quinolinecarboxylic acid; 7- [3S-amino-5S-ethyl-piperidinyl] -1-cyclopropyl-1,4-dihydro-6-fluoro-8-methoxy-4-oxo-3-quinolinecarboxylic acid; 7- [3S-amino-5R-ethyl-piperidinyl] -1-cyclopropyl-1,4-dihydro-6-fluoro-8-methoxy-4-oxo-3-quinolinecarboxylic acid; 7- [3S-amino-5S-methoxy-piperidinyl] -1-cyclopropyl-1,4-dihydro-6-fluoro-8-methoxy-4-oxo-3-quinolinecarboxylic acid; 7- [3S-amino-5R-methoxy-piperidinyl] -1-cyclopropyl-1,4-dihydro-6-fluoro-8-methoxy-4-oxo-3-quinolinecarboxylic acid; 7- [3S-amino-5,5-dimethyl-piperidinyl] -1-cyclopropyl-1,4-dihydro-6-fluoro-8-methoxy-4-oxo-3-quinolinecarboxyl mountain; 7- [3S-amino-5,5-diethyl-piperidinyl] -1-cyclopropyl-1,4-dihydro-6-fluoro-8-methoxy-4-oxo-3-quinolinecarboxyl mountain; 7- [3S-amino-4S-methyl-5R-methyl-piperidinyl] -1-cyclopropyl-1,4-dihydro-6-fluoro-8-methoxy-4-oxo-3-quinolinecar Acid; 7- [3S-amino-4S-ethyl-5R-methyl-piperidinyl] -1-cyclopropyl-1,4-dihydro-6-fluoro-8-methoxy-4-oxo-3-quinolinecar Acid; 7- [3S-amino-4S-isopropyl-5R-methyl-piperidinyl] -1-cyclopropyl-1,4-dihydro-6-fluoro-8-methoxy-4-oxo-3-quinoline Carboxylic acid; 7- [7-amino-5-azaspiro [2.5] -octanyl] -1-cyclopropyl-1,4-dihydro-6-fluoro-8-methoxy-4-oxo-3-quinolinecarboxyl mountain; 7- [7-amino-8S-methyl-5-azaspiro [2.5] -octanyl] -1-cyclopropyl-1,4-dihydro-6-fluoro-8-methoxy-4-oxo-3 -Quinolinecarboxylic acid; 7- [7-amino-8S-ethyl-5-azaspiro [2.5] -octanyl] -1-cyclopropyl-1,4-dihydro-6-fluoro-8-methoxy-4-oxo-3 -Quinolinecarboxylic acid; 7- [8-amino-6-azaspiro [3.5] -nonanyl] -1-cyclopropyl-1,4-dihydro-6-fluoro-8-methoxy-4-oxo-3-quinolinecarboxyl mountain; 7- [8-amino-9S-methyl-6-azaspiro [3.5] -nonanyl] -1-cyclopropyl-1,4-dihydro-6-fluoro-8-methoxy-4-oxo-3 -Quinolinecarboxylic acid; 7- [3S-amino-5S-methyl-piperidinyl] -1-cyclopropyl-1,4-dihydro-6-fluoro-8-methyl-4-oxo-3-quinolinecarboxylic acid; 7- [3S-amino-5R-methyl-piperidinyl] -1-cyclopropyl-1,4-dihydro-6-fluoro-8-methyl-4-oxo-3-quinolinecarboxylic acid; 7- [3S-amino-5S-ethyl-piperidinyl] -1-cyclopropyl-1,4-dihydro-6-fluoro-8-methyl-4-oxo-3-quinolinecarboxylic acid; 7- [3S-amino-5R-ethyl-piperidinyl] -1-cyclopropyl-1,4-dihydro-6-fluoro-8-methyl-4-oxo-3-quinolinecarboxylic acid; 7- [3S-amino-5S-methoxy-piperidinyl] -1-cyclopropyl-1,4-dihydro-6-fluoro-8-methyl-4-oxo-3-quinolinecarboxylic acid; 7- [3S-amino-5R-methoxy-piperidinyl] -1-cyclopropyl-1,4-dihydro-6-fluoro-8-methyl-4-oxo-3-quinolinecarboxylic acid; 7- [3S-amino-5,5-dimethyl-piperidinyl] -1-cyclopropyl-1,4-dihydro-6-fluoro-8-methyl-4-oxo-3-quinolinecarboxylic acid ; 7- [3S-amino-5,5-diethyl-piperidinyl] -1-cyclopropyl-1,4-dihydro-6-fluoro-8-methyl-4-oxo-3-quinolinecarboxylic acid ; 7- [3S-amino-4S-methyl-5R-methyl-piperidinyl] -1-cyclopropyl-1,4-dihydro-6-fluoro-8-methyl-4-oxo-3-quinolinecarboxyl mountain; 7- [3S-amino-4S-ethyl-5R-methyl-piperidinyl] -1-cyclopropyl-1,4-dihydro-6-fluoro-8-methyl-4-oxo-3-quinolinecarboxyl mountain; 7- [3S-amino-4S-isopropyl-5R-methyl-piperidinyl] -1-cyclopropyl-1,4-dihydro-6-fluoro-8-methyl-4-oxo-3-quinolinecar Acid; 7- [7-amino-5-azaspiro [2.5] -octanyl] -1-cyclopropyl-1,4-dihydro-6-fluoro-8-methyl-4-oxo-3-quinolinecarboxylic acid ; 7- [7-amino-8S-methyl-5-azaspiro [2.5] -octanyl] -1-cyclopropyl-1,4-dihydro-6-fluoro-8-methyl-4-oxo-3- Quinolinecarboxylic acid; 7- [7-amino-8S-ethyl-5-azaspiro [2.5] -octanyl] -1-cyclopropyl-1,4-dihydro-6-fluoro-8-methyl-4-oxo-3- Quinolinecarboxylic acid; 7- [8-amino-6-azaspiro [3.5] -nonanyl] -1-cyclopropyl-1,4-dihydro-6-fluoro-8-methyl-4-oxo-3-quinolinecarboxylic acid ; 7- [8-amino-9S-methyl-6-azaspiro [3.5] -nonanyl] -1-cyclopropyl-1,4-dihydro-6-fluoro-8-methyl-4-oxo-3- Quinolinecarboxylic acid; 7- [3S-amino-5S-methyl-piperidinyl] -1-cyclopropyl-1,4-dihydro-6-hydroxy-8-chloro-4-oxo-3-quinolinecarboxylic acid; 7- [3S-amino-5R-methyl-piperidinyl] -1-cyclopropyl-1,4-dihydro-6-hydroxy-8-chloro-4-oxo-3-quinolinecarboxylic acid; 7- [3S-amino-5S-ethyl-piperidinyl] -1-cyclopropyl-1,4-dihydro-6-hydroxy-8-chloro-4-oxo-3-quinolinecarboxylic acid; 7- [3S-amino-5R-ethyl-piperidinyl] -1-cyclopropyl-1,4-dihydro-6-hydroxy-8-chloro-4-oxo-3-quinolinecarboxylic acid; 7- [3S-amino-5S-methoxy-piperidinyl] -1-cyclopropyl-1,4-dihydro-6-hydroxy-8-chloro-4-oxo-3-quinolinecarboxylic acid; 7- [3S-amino-5R-methoxy-piperidinyl] -1-cyclopropyl-1,4-dihydro-6-hydroxy-8-chloro-4-oxo-3-quinolinecarboxylic acid; 7- [3S-amino-5,5-dimethyl-piperidinyl] -1-cyclopropyl-1,4-dihydro-6-hydroxy-8-chloro-4-oxo-3-quinolinecarboxylic acid ; 7- [3S-amino-5,5-diethyl-piperidinyl] -1-cyclopropyl-1,4-dihydro-6-hydroxy-8-chloro-4-oxo-3-quinolinecarboxylic acid ; 7- [3S-amino-4S-methyl-5R-methyl-piperidinyl] -1-cyclopropyl-1,4-dihydro-6-hydroxy-8-chloro-4-oxo-3-quinolinecarboxyl mountain; 7- [3S-amino-4S-ethyl-5R-methyl-piperidinyl] -1-cyclopropyl-1,4-dihydro-6-hydroxy-8-chloro-4-oxo-3-quinolinecarboxyl mountain; 7- [3S-amino-4S-isopropyl-5R-methyl-piperidinyl] -1-cyclopropyl-1,4-dihydro-6-hydroxy-8-chloro-4-oxo-3-quinolinecar Acid; 7- [7-amino-5-azaspiro [2.5] -octanyl] -1-cyclopropyl-1,4-dihydro-6-hydroxy-8-chloro-4-oxo-3-quinolinecarboxylic acid ; 7- [7-amino-8S-methyl-5-azaspiro [2.5] -octanyl] -1-cyclopropyl-1,4-dihydro-6-hydroxy-8-chloro-4-oxo-3- Quinolinecarboxylic acid; 7- [7-amino-8S-ethyl-5-azaspiro [2.5] -octanyl] -1-cyclopropyl-1,4-dihydro-6-hydroxy-8-chloro-4-oxo-3- Quinolinecarboxylic acid; 7- [8-amino-6-azaspiro [3.5] -nonanyl] -1-cyclopropyl-1,4-dihydro-6-hydroxy-8-chloro-4-oxo-3-quinolinecarboxylic acid ; 7- [8-amino-9S-methyl-6-azaspiro [3.5] -nonanyl] -1-cyclopropyl-1,4-dihydro-6-hydroxy-8-chloro-4-oxo-3- Quinolinecarboxylic acid; 8- [3S-amino-5S-methyl-piperidinyl] -1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid; 8- [3S-amino-5R-methyl-piperidinyl] -1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid; 8- [3S-amino-5S-ethyl-piperidinyl] -1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid; 8- [3S-amino-5R-ethyl-piperidinyl] -1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid; 8- [3S-amino-5S-methoxy-piperidinyl] -1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid; 8- [3S-amino-5R-methoxy-piperidinyl] -1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid; 8- [3S-amino-5,5-dimethyl-piperidinyl] -1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid; 8- [3S-amino-5,5-diethyl-piperidinyl] -1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid; 8- [3S-amino-4S-methyl-5R-methyl-piperidinyl] -1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid; 8- [3S-amino-4S-ethyl-5R-methyl-piperidinyl] -1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid; 8- [3S-amino-4S-isopropyl-5R-methyl-piperidinyl] -1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid ; 8- [7-amino-5-azaspiro [2.5] -octanyl] -1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid; 8- [7-amino-8S-methyl-5-azaspiro [2.5] -octanyl] -1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carbox Acid 8- [7-amino-8S-ethyl-5-azaspiro [2.5] -octanyl] -1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carbox Acid; 8- [8-amino-6-azaspiro [3.5] -nonanyl] -1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid; 8- [8-amino-9S-methyl-6-azaspiro [3.5] -nonanyl] -1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carbox Acid; 7- [3S-amino-5S-methyl-piperidinyl] -3-amino-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazolin-2,4-dione; 7- [3S-amino-5R-methyl-piperidinyl] -3-amino-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazolin-2,4-dione; 7- [3S-amino-5S-ethyl-piperidinyl] -3-amino-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazolin-2,4-dione; 7- [3S-amino-5R-ethyl-piperidinyl] -3-amino-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazolin-2,4-dione; 7- [3S-amino-5S-methoxy-piperidinyl] -3-amino-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazolin-2,4-dione; 7- [3S-amino-5R-methoxy-piperidinyl] -3-amino-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazolin-2,4-dione; 7- [3S-amino-5,5-dimethyl-piperidinyl] -3-amino-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazolin-2,4-dione; 7- [3S-amino-5,5-diethyl-piperidinyl] -3-amino-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazolin-2,4-dione; 7- [3S-amino-4S-methyl-5R-methyl-piperidinyl] -3-amino-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazolin-2,4-dione; 7- [3S-amino-4S-ethyl-5R-methyl-piperidinyl] -3-amino-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazolin-2,4-dione; 7- [3S-amino-4S-isopropyl-5R-methyl-piperidinyl] -3-amino-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazolin-2,4-dione ; 7- [7-amino-5-azaspiro [2.5] -octanyl] -3-amino-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazolin-2,4-dione; 7- [7-amino-8S-methyl-5-azaspiro [2.5] -octanyl]-3-amino-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazolin-2,4- Dion 7- [7-amino-8S-ethyl-5-azaspiro [2.5] -octanyl] -3-amino-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazolin-2,4- Diones; 7- [8-amino-6-azaspiro [3.5] -nonanyl]-3-amino-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazolin-2,4-dione; 7- [8-amino-9S-methyl-6-azaspiro [3.5] -nonanyl]-3-amino-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazolin-2,4- A compound selected from the group consisting of dions. Pharmaceutical compositions containing: (a) a safe and effective amount of the compound of any one of claims 1 to 8, (b) Pharmaceutically acceptable excipients. Use of a compound according to any one of claims 1 to 8 in the manufacture of a medicament for preventing or treating a microbial infection in a subject in need thereof.